Objective:We aimed to directly compare the estimated effects of adherence to a healthy lifestyle with those of risk predisposition according to known genetic variants affecting colorectal cancer(CRC)risk,to support ef...Objective:We aimed to directly compare the estimated effects of adherence to a healthy lifestyle with those of risk predisposition according to known genetic variants affecting colorectal cancer(CRC)risk,to support effective risk communication for cancer prevention.Methods:A healthy lifestyle score(HLS)was derived from 5 lifestyle factors:smoking,alcohol consumption,diet,physical activity,and body adiposity.The association of lifestyle and polygenic risk score(PRS)(based on 140 CRC-associated risk loci)with CRC risk was assessed with multiple logistic regression and compared through the genetic risk equivalent(GRE),a novel approach providing an estimate of the effects of adherence to a healthy lifestyle in terms of percentile differences in PRS.Results:A higher HLS was associated with lower CRC risk(4,844 cases,3,964 controls).Those adhering to all 5 healthy lifestyle factors had a 62%(95%CI 54%-68%)lower CRC risk than those adhering to≤2 healthy lifestyle factors.The estimated effect of adherence to all 5 compared with≤2 healthy lifestyle factors was as strong as the effect of having a 79 percentile(GRE 79,95%CI 61-97)lower PRS.The association between a healthy lifestyle and CRC risk was independent of PRS level but was particularly pronounced among those with a family history of CRC in≥1 first-degree relative(P-interaction=0.0013).Conclusions:A healthy lifestyle was strongly inversely associated with CRC risk.The large GRE indicated that CRC risk determined by polygenic risk may be offset to a substantial extent by adherence to a healthy lifestyle.展开更多
Background: Inhibition of the lymphoma surface antigen CD40 by the antagonistic CD40 antibody NVP-HCD122 (HCD122) demonstrates activity in various lymphoma subtypes. In this preclinical in vivo study we examined the s...Background: Inhibition of the lymphoma surface antigen CD40 by the antagonistic CD40 antibody NVP-HCD122 (HCD122) demonstrates activity in various lymphoma subtypes. In this preclinical in vivo study we examined the suitability of positron emission tomography (PET) using the thymidine analogue 3’-deoxy-3’-[18F]fluorothymidine (FLT) for early response assessment upon HCD122 treatment in diffuse large B cell lymphoma (DLBCL). Methods: Immunodeficient mice bearing human DLBCL xenografts (SU-DHL-4) received weekly intraperitoneal injections of HCD122. Tumor growth was followed up until Day 14. Molecular imaging with FLT-PET was performed before (Day 0) and after start of therapy (Day 2 and Day 7). On Day 14 lymphoma xenografts were explanted for immunohistochemical analysis to correlate PET findings with CD40 surface expression on tumor tissue. Results: Treatment with HCD122 significantly delayed tumor growth resulting in a tumor growth inhibition of 45% on Day 14. Significant reduction of tumor-to-background ratio (TBR) of FLT-PET was seen in treated animals on Day 7 and preceded change of tumor volume, thus predicting therapy response to HCD122. Immunohistochemical analysis of xenografts revealed significantly higher CD40 expression on treated than on untreated tissue. Moreover, we found a significant correlation between CD40 expression and FLT-PET response for xenograft tumor treated with HCD122. Conclusions: Treatment of DLBCL with the antagonistic CD40 antibody HCD122 can be monitored with FLT-PET as early as seven days after commencement of therapy and seems to increase CD40 expression on tumor tissue.展开更多
Understanding the interplay between oncogenic mutations and the tumor microenvironment could help improve therapy for hematological malignancies.We found that the STAT5-activating oncogenes JAK2 p.V617F,FLT3-ITD,and B...Understanding the interplay between oncogenic mutations and the tumor microenvironment could help improve therapy for hematological malignancies.We found that the STAT5-activating oncogenes JAK2 p.V617F,FLT3-ITD,and BCR::ABL1 induce oncostatin M(OSM),which triggers disease progression and immunosuppression.The OSM receptor was predominantly expressed on nonhematopoietic bone marrow(BM)stromal cells.OSM reprogrammed these cells via STAT3 and induced the secretion of cytokines connected to T-cell exhaustion,including IL-6 and MCP-1.Compared with control mice,OSM-overexpressing mice presented reduced T-cell numbers,increased levels of inhibitory receptors on T cells,and elevated lactic acid production by BM stromal cells.OSM induced the expansion of myeloid cells which suppressed T cells.Conversely,genetic deletion of Osm in a JAK2 p.V617F-driven polycythemia vera mouse model reduced polycythemia,BM fibrosis,inflammatory cytokine levels and the expression of inhibitory markers on T cells.Transcriptomic analyses of T cells from OSM-overexpressing mice revealed enrichment of IL6–JAK–STAT3 and inflammatory signaling pathways.Additionally,pharmacological inhibition of OSM reduced disease activity and cytokine production.These findings establish OSM as a key mediator linking oncogenic STAT5 activation to remodeling of the microenvironment and immune suppression.Targeting OSM signaling therefore represents a promising therapeutic strategy to alleviate disease progression in myeloproliferative neoplasms and related malignancies.展开更多
Both overall and abdominal obesity are well-established risk factors for various cancer types,including colorectal cancer(CRC)[1].However,how adiposity impacts CRC development has been insufficiently investigated.Thre...Both overall and abdominal obesity are well-established risk factors for various cancer types,including colorectal cancer(CRC)[1].However,how adiposity impacts CRC development has been insufficiently investigated.Three primary hypotheses have been suggested to elucidate the biological pathways that link adiposity and CRC:alterations in insulin signaling,dysregulation of adipose tissue-derived inflammation,and sex hormone metabolism[2,3].展开更多
Epithelioid sarcoma(EpS)is a high-grade malignancy of unknown histogenesis first described in 1970[1],characterized by high rates of relapse and metastasis,with 5-year survival rates of 60%-75%[2].The only Food and Dr...Epithelioid sarcoma(EpS)is a high-grade malignancy of unknown histogenesis first described in 1970[1],characterized by high rates of relapse and metastasis,with 5-year survival rates of 60%-75%[2].The only Food and Drug Administration(FDA)-approved targeted therapy,the enhancer of zeste homology 2(EZH2)inhibitor tazemetostat,achieved transient responses in only 15%of patients[2].展开更多
The B cell lymphoma 2(BCL2)protein family critically controls apoptosis by regulating the release of cytochrome c from mitochondria.In this cutting-edge review,we summarize the basic biology regulating the BCL2 family...The B cell lymphoma 2(BCL2)protein family critically controls apoptosis by regulating the release of cytochrome c from mitochondria.In this cutting-edge review,we summarize the basic biology regulating the BCL2 family including canonical and noncanonical functions,and highlight milestones from basic research to clinical applications in cancer and other pathophysiological conditions.We review laboratory and clinical development of BH3-mimetics as well as more recent approaches including proteolysis targeting chimeras(PROTACs),antibody-drug conjugates(ADCs)and tools targeting the BH4 domain of BCL2.The first BCL2-selective BH3-mimetic,venetoclax,showed remarkable efficacy with manageable toxicities and has transformed the treatment of several hematologic malignancies.Following its success,several chemically similar BCL2 inhibitors such as sonrotoclax and lisaftoclax are currently under clinical evaluation,alone and in combination.Genetic analysis highlights the importance of BCLX,and MCL1 across different cancer types and the possible utility of BH3-mimetics targeting these proteins.However,the development of BH3-mimetics targeting BCL-X_(L) or MCL1 has been more challenging,with on-target toxicities including thrombocytopenia for BCL-X_(L) and cardiac toxicities for MCL1 inhibitors precluding clinical development.Tumor-specific BCL-X_(L) or MCL1 inhibition may be achieved by novel targeting approaches using PROTACs or selective drug delivery strategies and would be transformational in many subtypes of malignancy.Taken together,we envision that the targeting of BCL2 proteins,while already a success story of translational research,may in the foreseeable future have broader clinical applicability and improve the treatment of multiple diseases.展开更多
Screening for colorectal cancer(CRC)is among the mosteffective approaches to cancer prevention,yet achievinghigh adherence to effective screening offers is challenging[1].Blood-based tests that could be easily impleme...Screening for colorectal cancer(CRC)is among the mosteffective approaches to cancer prevention,yet achievinghigh adherence to effective screening offers is challenging[1].Blood-based tests that could be easily implemented inroutine medical practice might be a promising approachto achieve higher adherence rates than with conven-tional stool-based or endoscopic screening[2,3].However,neoplasm detection rates of previously developed and pro-posed blood-based tests have not been competitive tothose of modern stool-based tests[2],in particular fecalimmunochemical tests(FITs)that are meanwhile widelyused for CRC screening in an increasing number of coun-tries[4].Most recently,performance of a novel cell-freeDNA(cfDNA)blood-based test for detecting colorectalneoplasms was validated in the ECLIPSE study,a largescreening population undergoing screening colonoscopy[5],being the first of its kind to achieve FDA approval asa primary screening option for CRC.展开更多
In a recent study published in Cancer Cell,Braun et al.introduced extracorporeal photopheresis(ECP)as a novel immunomodulatory approach to mitigate immune-related adverse events(irAEs)associated with immune checkpoint...In a recent study published in Cancer Cell,Braun et al.introduced extracorporeal photopheresis(ECP)as a novel immunomodulatory approach to mitigate immune-related adverse events(irAEs)associated with immune checkpoint inhibitors(ICIs)without compromising anti-tumor immunity.1 ECP suppressed Th1/Trm cell activation and neutrophil infiltration while enhancing an antiinflammatory macrophage phenotype through adiponectin,facilitating the resolution of steroid-refractory irAEs.展开更多
Based on intriguing findings from observational studies[1,2],colonoscopy has since long been recommended for colorectal cancer(CRC)screening,long before evidence on its effectiveness in reducing CRC incidence and mort...Based on intriguing findings from observational studies[1,2],colonoscopy has since long been recommended for colorectal cancer(CRC)screening,long before evidence on its effectiveness in reducing CRC incidence and mortality was demonstrated by a randomized controlled trial(RCT).Such evidence has only recently been provided by the Nordic-European Initiative on Colorectal Cancer(NordICC)trial[3].In this RCT,the risk of CRC was lower among those invited to undergo screening colonoscopy than among those not invited to screening.However,reported CRC risk reduction was smaller than anticipated:The authors derived risk ratios of 0.82(95%confidence interval[CI]=0.70-0.93)and 0.69(95%CI=0.55-0.83)in intention-to-screen analysis and adjusted per-protocol analysis,respectively,suggesting an 18%risk reduction of CRC among those invited for screening and a 31%risk reduction among screening attenders.展开更多
Intestinal stem cells(ISCs)promote tissue repair after genotoxic or immune-mediated injury.However,ISCs are particularly sensitive to various stressors and primary targets of overwhelming immune responses,such as inte...Intestinal stem cells(ISCs)promote tissue repair after genotoxic or immune-mediated injury.However,ISCs are particularly sensitive to various stressors and primary targets of overwhelming immune responses,such as interferonγ(IFNγ)-mediated killing.In mouse models of radiation therapy-induced gut damage and in biopsies from patients who underwent allogeneic hematopoietic stem cell transplantation,we observed IFNγexpression by intestinal Treg cells.Treg cells leverage combined IFNγand interleukin 10(IL-10)stimulation of ISCs to nurture the growth of intestinal organoids through the activation of the mTORC1 and Myc pathways.Similarly,Treg cells or the combined addition of recombinant IFNγand IL-10 promoted the regeneration of organoids after irradiation,and both cytokines were essential for ensuring epithelial regeneration following acute intestinal tissue injury in vivo.The exposure of organoids to growth factor-free culture conditions revealed distinct EGF-like properties of IFNγand Wnt-like properties of IL-10.While IFNγrapidly induced epithelial proliferation,it depleted the pool of ISCs in vitro.Only the combination of IFNγand IL10 led to epithelial proliferation and organoid growth while simultaneously ensuring ISC maintenance over time.Our results reveal a context-dependent role of inflammatory signaling in ISCs,through which Treg cells promote epithelial repair following therapyinduced injury.展开更多
Ovarian cancer,particularly high-grade serous ovariancancer(HGSOC),remains the most lethal gynecologicalmalignancy,with a 5-year survival rate of around 40%due to late diagnosis,recurrence,and the developmentof chemor...Ovarian cancer,particularly high-grade serous ovariancancer(HGSOC),remains the most lethal gynecologicalmalignancy,with a 5-year survival rate of around 40%due to late diagnosis,recurrence,and the developmentof chemoresistance[1,2].Mutations in tumor protein 53(TP53)occur in over 96%of HGSOC cases,impairing itstumor-suppressive functions,including cell cycle control,DNA repair,and apoptosis.Mutant TP53 promotes tumorprogression,genomic instability,and resistance to stan-dard therapies,thereby worsening patient outcomes[3,4].Death-associated protein kinase 1(DAPK1)is a key reg-ulator of apoptosis and autophagy[5,6].展开更多
In a recent publication in Cell,Hsu and colleagues describe a novel kind of extracellular vesicle that is involved in the resolution of inflammation.Such large_ageing_neutrophil-derived,vesicles(LAND-Vs)that express C...In a recent publication in Cell,Hsu and colleagues describe a novel kind of extracellular vesicle that is involved in the resolution of inflammation.Such large_ageing_neutrophil-derived,vesicles(LAND-Vs)that express CD55^(+) and CD47^(+) are protected against efferocytosis and exhibit anti-inflammatory functions by inhibiting the complement activation.These findings reveal an important functional switch of neutrophils throughout the course of inflammation and identify a novel class of EVs that mediate neutrophil action beyond their limited lifespan,which may open new modes of therapeutic interference in various inflammatory conditions.展开更多
Neutrophils have emerged as key players in tumor progression and are often associated with poor prognosis.Despite ongoing efforts to target neutrophil functions in cancer,therapeutic success has been limited.In this s...Neutrophils have emerged as key players in tumor progression and are often associated with poor prognosis.Despite ongoing efforts to target neutrophil functions in cancer,therapeutic success has been limited.In this study,we addressed the possibility of blocking STAT3 signaling in neutrophils as a targeted therapeutic intervention in cancer.Conditional deletion of Stat3 in a neutrophil-specific manner(Ly6GcreStat3fl/fl mice)significantly impaired tumor growth and metastasis in mice.Neutrophils isolated from these mice exhibited a strong antitumoral phenotype,with increased MHCII,CD80/86 and ICAM-1 expression.Immune profiling of tumors and tumor-draining lymph nodes of these mice revealed significant enrichment of CD8^(+)T cells(granzymeB^(hi),perforin^(hi) and IFN-γ^(hi))with strong cytotoxic activity.To further translate these findings to human settings,we blocked STAT3 signaling in cancer patient neutrophils via the small molecule in^(hi)bitor LLL12 and assessed its effects on patient-derived tumor explants.In agreement with the in vivo mouse data,we observed the expansion and activation of cytotoxic CD8^(+)T cells in such explants.To test the therapeutic applicability of STAT3 targeting,we utilized myeloid cell-selective STAT3 antisense oligonucleotide(CpG-STAT3ASO)to target neutrophils in vivo in tumor-bearing mice.Consistent with previous results,neutrophil-specific STAT3 knockdown impaired tumor growth and enhanced cytotoxic T cell activity in the tumors and tumor-draining lymph nodes of treated mice.These findings highlight STAT3 signaling as a deleterious pathway supporting the protumoral activity of neutrophils and suggest that neutrophil-targeted STAT3 in^(hi)bition is a promising opportunity for cancer immunotherapy,providing novel insights into targeted therapeutic avenues.展开更多
A recent publication by Geraghty et al.in Cell investigates how chimeric antigen receptor(CAR)T cell therapy can induce cognitive impairment in murine models of both central nervous system(CNS)-and non-CNS-based tumor...A recent publication by Geraghty et al.in Cell investigates how chimeric antigen receptor(CAR)T cell therapy can induce cognitive impairment in murine models of both central nervous system(CNS)-and non-CNS-based tumors.1 The authors identified persistent neuroinflammation as a key mechanism underlying these cognitive deficits and successfully explored novel therapeutic strategies,including microglial depletion and CCR3 blockade(Fig.1).1.展开更多
In their recently published study in Science,Popow and colleagues developed a proteolysis-targeting chimera(PROTAC)for the in vivo degradation of several oncogenic KRAS variants^(1).Leveraging detailed biophysical ana...In their recently published study in Science,Popow and colleagues developed a proteolysis-targeting chimera(PROTAC)for the in vivo degradation of several oncogenic KRAS variants^(1).Leveraging detailed biophysical analyses and crystal structures of ternary complexes of candidate ligands for KRAS and the von Hippei-Lindau(VHL)E3 ubiquitin ligase complex,they designed a small molecule capable of potently and selectively targeting 13 of the 17 most common KRAS mutants.展开更多
Pilocytic astrocytomas(PA),the most common pediatric low-grade gliomas(pLGGs),are characterized by genetic MAPK pathway alterations leading to constitutive activation and oncogene-induced senescence(OIS)accompanied wi...Pilocytic astrocytomas(PA),the most common pediatric low-grade gliomas(pLGGs),are characterized by genetic MAPK pathway alterations leading to constitutive activation and oncogene-induced senescence(OIS)accompanied with the senescence-associated secretory phenotype(SASP).This study investigates the molecular mechanisms of signaling pathways regulating OIS and SASP in pLGGs using a multi-omics approach.We utilized senescent DKFZ-BT66 cells derived from a primary KIAA1549::BRAF-fusion positive PA to generate RNA-sequencing and phospho-/proteomic datasets before and after treatment with the MEK inhibitor trametinib.Multi-omics factor analysis(MEFISTO)and single sample gene set enrichment analysis(ssGSEA)were employed to identify key OIS effectors and differentially regulated pathways upon MAPK inhibition.Trametinib treatment inhibited MAPK activity,OIS and SASP signatures across all omics levels,functionally underscored by reduced sensitivity towards senolytic drugs.We constructed a pathway network using a prior knowledge approach,mapping n=106 upregulated and n=84 downregulated direct downstream effectors of MAPK leading to OIS/SASP.These effectors are associated with better progression-free survival in pLGG patients,independent of tumor site,level of resection,and genetic aberration.Several compounds targeting signaling nodes(SOD-1,IRS1,CDK1/2,CK2)involved in OIS and under MAPK control were identified,of which n=4 were validated in an additional primary KIAA1549::BRAF fusion pLGG model as potential new therapeutic vulnerabilities for the treatment of pLGG.Our unbiased multiomics signaling pathway analysis identifies a specific and comprehensive network of MAPK-OIS-SASP interdependencies in pLGGs and suggests new therapeutic strategies for these tumors.展开更多
Leucine-rich repeat containing 15(LRRC15)has emerged as an attractive biomarker and target for cancer therapy.Transforming growth factor-β(TGFβ)induces the expression of this plasma membrane protein specifically in ...Leucine-rich repeat containing 15(LRRC15)has emerged as an attractive biomarker and target for cancer therapy.Transforming growth factor-β(TGFβ)induces the expression of this plasma membrane protein specifically in aggressive and treatment resistant tumor cells derived from mesenchymal stem cells,with minimal expression observed in non-neoplastic tissues.We have developed a humanized monoclonal antibody,DUNP19,that specifically binds with high affinity to a phylogenetically conserved LRRC15 epitope and is rapidly internalized upon LRRC15 binding.In multiple subcutaneous and orthotopic tumor xenograft mouse models,Lutetium-177 labeled DUNP19([^(177)Lu]Lu-DUNP19)enabled non-invasive imaging and molecularly precise radiotherapy to LRRC15-expressing cancer cells and murine cancer-associated fibroblasts,effectively halting tumor progression and prolonging survival with minimal toxicity.Transcriptomic analyses of[^(177)Lu]Lu-DUNP19-treated tumors reveal a loss of pro-tumorigenic mechanisms,including a previously reported TGF β-induced LRRC15+signature associated with immunotherapy resistance.In a syngeneic tumor model,administration of[^(177)Lu]Lu-DUNP19 significantly potentiated checkpoint-blockade therapy,yielding durable complete responses.Together,these results demonstrate that radio-theranostic targeting of LRRC15 with DUNP19 is a compelling precision medicine platform for image-guided diagnosis,eradication,and reprogramming of LRRC15+tumor tissue that drives immunoresistance and disease aggressiveness in a wide range of currently untreatable malignancies.展开更多
Immunotherapy is currently one of the most promising treatment options for malignant melanoma[1].To uncover new immunological targets for future treatment approaches,single-cell transcriptomic and epigenomic analyses ...Immunotherapy is currently one of the most promising treatment options for malignant melanoma[1].To uncover new immunological targets for future treatment approaches,single-cell transcriptomic and epigenomic analyses were performed on human primary melanoma(MM)and melanocytic nevus(Nev)samples(Figure 1A).展开更多
In the tumor host,neutrophils may exhibit protumor or antitumor activity.It is hypothesized that in response to host-derived or therapy-induced factors,neutrophils adopt diverse functional states to ultimately execute...In the tumor host,neutrophils may exhibit protumor or antitumor activity.It is hypothesized that in response to host-derived or therapy-induced factors,neutrophils adopt diverse functional states to ultimately execute these differential functions.Here,we provide an alternative scenario in which the response of an individual tumor cell population determines the overall protumor versus antitumor outcome of neutrophil‒tumor interactions.Experimentally,we show that human neutrophils,which are sequentially stimulated with bacteria and secreted factors from tumor cells,kill a certain proportion of tumor target cells.However,the majority of the tumor cells remained resistant to this neutrophil-mediated killing and underwent a functional,phenotypic and transcriptomic switch that was reminiscent of partial epithelial‒to-mesenchymal transition.This cell biological switch was associated with physical escape from NK-mediated killing and resulted in enhanced metastasis to the lymph nodes in a preclinical orthotopic mouse model.Mechanistically,we identified the antimicrobial neutrophil granule proteins neutrophil elastase(NE)and matrix metalloprotease-9(MMP-9)as the molecular mediators of this functional switch.We validated these data in patients with head and neck cancer and identified bacterially colonized intratumoral niches that were enriched for mesenchymal tumor cells and neutrophils expressing NE and MMP-9.Our data reveal the parallel execution of tumor cytotoxic and prometastatic activity by activated neutrophils and identify NE and MMP-9 as mediators of lymph node metastasis.The identified mechanism explains the functional dichotomy of tumor-associated neutrophils at the level of the tumor target cell response and has implications for superinfected cancers and the dysbiotic tumor microenvironment.展开更多
基金supported by the Guangzhou Elite Project (GEP)supported by grants from the German Research Council (Grant Nos. BR 1704/6-1, BR1704/6-3, BR 1704/6-4, BR 1704/6-6, CH 117/1-1, and BR 1704/17-1, HO 5117/2-1)the German Federal Ministry of Education and Research (Grant Nos. 01KH0404, 01ER0814, 01ER0815, and 01GL1712)
文摘Objective:We aimed to directly compare the estimated effects of adherence to a healthy lifestyle with those of risk predisposition according to known genetic variants affecting colorectal cancer(CRC)risk,to support effective risk communication for cancer prevention.Methods:A healthy lifestyle score(HLS)was derived from 5 lifestyle factors:smoking,alcohol consumption,diet,physical activity,and body adiposity.The association of lifestyle and polygenic risk score(PRS)(based on 140 CRC-associated risk loci)with CRC risk was assessed with multiple logistic regression and compared through the genetic risk equivalent(GRE),a novel approach providing an estimate of the effects of adherence to a healthy lifestyle in terms of percentile differences in PRS.Results:A higher HLS was associated with lower CRC risk(4,844 cases,3,964 controls).Those adhering to all 5 healthy lifestyle factors had a 62%(95%CI 54%-68%)lower CRC risk than those adhering to≤2 healthy lifestyle factors.The estimated effect of adherence to all 5 compared with≤2 healthy lifestyle factors was as strong as the effect of having a 79 percentile(GRE 79,95%CI 61-97)lower PRS.The association between a healthy lifestyle and CRC risk was independent of PRS level but was particularly pronounced among those with a family history of CRC in≥1 first-degree relative(P-interaction=0.0013).Conclusions:A healthy lifestyle was strongly inversely associated with CRC risk.The large GRE indicated that CRC risk determined by polygenic risk may be offset to a substantial extent by adherence to a healthy lifestyle.
文摘Background: Inhibition of the lymphoma surface antigen CD40 by the antagonistic CD40 antibody NVP-HCD122 (HCD122) demonstrates activity in various lymphoma subtypes. In this preclinical in vivo study we examined the suitability of positron emission tomography (PET) using the thymidine analogue 3’-deoxy-3’-[18F]fluorothymidine (FLT) for early response assessment upon HCD122 treatment in diffuse large B cell lymphoma (DLBCL). Methods: Immunodeficient mice bearing human DLBCL xenografts (SU-DHL-4) received weekly intraperitoneal injections of HCD122. Tumor growth was followed up until Day 14. Molecular imaging with FLT-PET was performed before (Day 0) and after start of therapy (Day 2 and Day 7). On Day 14 lymphoma xenografts were explanted for immunohistochemical analysis to correlate PET findings with CD40 surface expression on tumor tissue. Results: Treatment with HCD122 significantly delayed tumor growth resulting in a tumor growth inhibition of 45% on Day 14. Significant reduction of tumor-to-background ratio (TBR) of FLT-PET was seen in treated animals on Day 7 and preceded change of tumor volume, thus predicting therapy response to HCD122. Immunohistochemical analysis of xenografts revealed significantly higher CD40 expression on treated than on untreated tissue. Moreover, we found a significant correlation between CD40 expression and FLT-PET response for xenograft tumor treated with HCD122. Conclusions: Treatment of DLBCL with the antagonistic CD40 antibody HCD122 can be monitored with FLT-PET as early as seven days after commencement of therapy and seems to increase CD40 expression on tumor tissue.
基金We thank the Lighthouse Core Facility(LCF)for their support with cell sorting and FACS.LCF is funded in part by the Medical Faculty,University of Freiburg(Project Numbers 2021/A2-Fol,2021/B3-Fol)the DFG(Project Number 450392965)+14 种基金supported by the Deutsche Forschungsgemeinschaft(DFG),Germany,CRC1479-Project ID:441891347 to J.D.,M.R.,K.A.C.,O.G.,N.C.,M.B.,N.K.,M.Z.,L.I.and R.Z.M.R.,T.A.M.and J.D.were funded by collaborative research projects from the DFG,FOR20233 B1 and B3M.R.was supported by the DFG RA 3488/1-1T.A.M.by a research grant from the German JoséCarreras Leukemia Foundation(DJCLS 02 FN/2017)T.N.H.and D.A.were also supported by the German JoséCarreras Leukemia Foundation(DJCLS 04 R/2020)the Bundesministerium für Bildung und Forschung(BMBF)6LW0711We further acknowledge funding from the DFG within the CRC1160(Project ID 256073931-Z02 to O.G.and M.B.,B09 to N.K.and R.Z.),CRC/TRR167(Project ID 259373024-Z01,M.B.,O.G.),CRC1453(Project ID 431984000-S1,M.B.),and CRC1425(Project ID 422681845,O.G.)M.B.received funding from TRR 359(Project ID 491676693-Z01)FOR 5476 UcarE(Project ID 493802833-P7)We also acknowledge funding from the German Federal Ministry of Education and Research(BMBF)within the Medical Informatics Funding Scheme,PM4Onco-FKZ 01ZZ2322A(M.B.)and EkoEstMed-FKZ 01ZZ2015(G.A.)Funding for O.G.was received within GRK2606(Project ID 423813989)under Germany’s Excellence Strategy,through CIBSS-EXC-2189(Project ID 390939984)by the European Research Council(ERC)through Starting Grant 337689,Proof-of-Concept Grant 966687,and the EU-H2020-MSCA-COFUND EURIdoc programme(No.101034170)A.L.I.was supported by the Mildred-Scheel-Professorship from the German Cancer Aid(DKH-70114112)the German Ministry of Research,Technology and Space(01KD2403)the EU(MSCADN 101071735).
文摘Understanding the interplay between oncogenic mutations and the tumor microenvironment could help improve therapy for hematological malignancies.We found that the STAT5-activating oncogenes JAK2 p.V617F,FLT3-ITD,and BCR::ABL1 induce oncostatin M(OSM),which triggers disease progression and immunosuppression.The OSM receptor was predominantly expressed on nonhematopoietic bone marrow(BM)stromal cells.OSM reprogrammed these cells via STAT3 and induced the secretion of cytokines connected to T-cell exhaustion,including IL-6 and MCP-1.Compared with control mice,OSM-overexpressing mice presented reduced T-cell numbers,increased levels of inhibitory receptors on T cells,and elevated lactic acid production by BM stromal cells.OSM induced the expansion of myeloid cells which suppressed T cells.Conversely,genetic deletion of Osm in a JAK2 p.V617F-driven polycythemia vera mouse model reduced polycythemia,BM fibrosis,inflammatory cytokine levels and the expression of inhibitory markers on T cells.Transcriptomic analyses of T cells from OSM-overexpressing mice revealed enrichment of IL6–JAK–STAT3 and inflammatory signaling pathways.Additionally,pharmacological inhibition of OSM reduced disease activity and cytokine production.These findings establish OSM as a key mediator linking oncogenic STAT5 activation to remodeling of the microenvironment and immune suppression.Targeting OSM signaling therefore represents a promising therapeutic strategy to alleviate disease progression in myeloproliferative neoplasms and related malignancies.
基金funding from British Heart Foundation,Cancer Research UK,Diabetes UK,and National Institute for Health Research(NIHR)supported by the National Health Service(NHS).
文摘Both overall and abdominal obesity are well-established risk factors for various cancer types,including colorectal cancer(CRC)[1].However,how adiposity impacts CRC development has been insufficiently investigated.Three primary hypotheses have been suggested to elucidate the biological pathways that link adiposity and CRC:alterations in insulin signaling,dysregulation of adipose tissue-derived inflammation,and sex hormone metabolism[2,3].
基金supported by a grant from the SMARCB1 associationsupported by grants from the Dr.Rolf M.Schwiete foundation(2021-007,2022-031)+11 种基金the Matthias-Lackas foundationthe Dr.Leopold und Carmen Ellinger foundationthe Deutsche Forschungsgemeinschaft(DFG 458891500)the Cancer Grand Challenges project PROTECTthe German Cancer Aid(DKH-7011411,DKH-70114278,DKH-70115315,DKH-70115914)the Ministry of Education and Research(BMBF,SMART-CARE and HEROES-AYA)the KiKa foundation(#486)the Fight Kids Cancer foundation(FKC-NEWtargets)the KiTZ-Foundation in memory of Kirstin Diehl,the KiTZPMC twinning programthe German Cancer Consortium(DKTK,PRedictAHR)the Barbara and Wilfried Mohr foundationThe laboratory of Thomas G.P.Grünewald is co-funded by the European Union(ERC,CANCERHARAKIRI,101122595).
文摘Epithelioid sarcoma(EpS)is a high-grade malignancy of unknown histogenesis first described in 1970[1],characterized by high rates of relapse and metastasis,with 5-year survival rates of 60%-75%[2].The only Food and Drug Administration(FDA)-approved targeted therapy,the enhancer of zeste homology 2(EZH2)inhibitor tazemetostat,achieved transient responses in only 15%of patients[2].
基金supported by the Deutsche Krebshilfe(to M.V.)the Wilhelm Sander Stiftung(to M.V.)+13 种基金the Deutsche Kinderkrebsstiftung(to M.V)the Deutsche Jose Carreras Leukamie-Stiftung(to M.V and S.M.)research funding from LOxO(to V.M.S)Y.B.is supported by a Junior Clinician Scientist grant of the Goethe-University Frankfurt and by funds of the Rudolf-GeiBendorfer-StiftungWork in MJSD lab is supported by funds from the Scott-Waudby Trustthe Hope Against Cancer charity,Cancer Research UK in conjunction with the UK Department of Health on an Experimental Cancer Medicine Center grant[MRC]by Leicester Drug Discovery and Diagnostics under the University of Leicester Institute for Precision Health[MRC-Impact Acceleration AccountMR/X502777/1]is carried out at the National Institute for Health and Care Research(NIHR)Leicester Biomedical Research Center(BRC).Additional funding was obtained from Beigene and LOXO pharmaWork in the G.B.lab is funded by grants from the Research Foundation Flanders(GOE7520N,G081821N and G094522 N)from the Research Council,KU Leuven(C14/19/099)the Central European Leuven Strategic Alliance(CELSA/23/031and CELSA/23/032)GB is member of the FWO Scientific Research Network CaSign(W0.014.22N)MC(application number 11K7122N)and TV(application number:12ZG121N)were supported by fellowships from the Research Foundation FlandersWork in SM lab is supported by project PI20/00328 from the Instituto de Salud Carlos ll(Spain)and the M.C.AndreuMemorialFund.
文摘The B cell lymphoma 2(BCL2)protein family critically controls apoptosis by regulating the release of cytochrome c from mitochondria.In this cutting-edge review,we summarize the basic biology regulating the BCL2 family including canonical and noncanonical functions,and highlight milestones from basic research to clinical applications in cancer and other pathophysiological conditions.We review laboratory and clinical development of BH3-mimetics as well as more recent approaches including proteolysis targeting chimeras(PROTACs),antibody-drug conjugates(ADCs)and tools targeting the BH4 domain of BCL2.The first BCL2-selective BH3-mimetic,venetoclax,showed remarkable efficacy with manageable toxicities and has transformed the treatment of several hematologic malignancies.Following its success,several chemically similar BCL2 inhibitors such as sonrotoclax and lisaftoclax are currently under clinical evaluation,alone and in combination.Genetic analysis highlights the importance of BCLX,and MCL1 across different cancer types and the possible utility of BH3-mimetics targeting these proteins.However,the development of BH3-mimetics targeting BCL-X_(L) or MCL1 has been more challenging,with on-target toxicities including thrombocytopenia for BCL-X_(L) and cardiac toxicities for MCL1 inhibitors precluding clinical development.Tumor-specific BCL-X_(L) or MCL1 inhibition may be achieved by novel targeting approaches using PROTACs or selective drug delivery strategies and would be transformational in many subtypes of malignancy.Taken together,we envision that the targeting of BCL2 proteins,while already a success story of translational research,may in the foreseeable future have broader clinical applicability and improve the treatment of multiple diseases.
基金funded by grants from the GermanResearch Council(DFG,grant No.BR1704/16-1)the Fed-eral Ministry of Education and Research(BMBF,grantno.01GL1712 and 01KD2104A)the German CancerAid(No.70113330).
文摘Screening for colorectal cancer(CRC)is among the mosteffective approaches to cancer prevention,yet achievinghigh adherence to effective screening offers is challenging[1].Blood-based tests that could be easily implemented inroutine medical practice might be a promising approachto achieve higher adherence rates than with conven-tional stool-based or endoscopic screening[2,3].However,neoplasm detection rates of previously developed and pro-posed blood-based tests have not been competitive tothose of modern stool-based tests[2],in particular fecalimmunochemical tests(FITs)that are meanwhile widelyused for CRC screening in an increasing number of coun-tries[4].Most recently,performance of a novel cell-freeDNA(cfDNA)blood-based test for detecting colorectalneoplasms was validated in the ECLIPSE study,a largescreening population undergoing screening colonoscopy[5],being the first of its kind to achieve FDA approval asa primary screening option for CRC.
基金German Cancer Aid(Max-Eder Junior Research Group,ref.70115384)'funded by the Clinician Scientist Program of Heidelberg University,Faculty of Medicine and is part of the Cancer Core Europe(CCE)Training program of Young leaders in TRAnslational Cancer research(TRYTRAC).
文摘In a recent study published in Cancer Cell,Braun et al.introduced extracorporeal photopheresis(ECP)as a novel immunomodulatory approach to mitigate immune-related adverse events(irAEs)associated with immune checkpoint inhibitors(ICIs)without compromising anti-tumor immunity.1 ECP suppressed Th1/Trm cell activation and neutrophil infiltration while enhancing an antiinflammatory macrophage phenotype through adiponectin,facilitating the resolution of steroid-refractory irAEs.
基金supported in part by grants from the German Federal Ministry of Education and Research(grant no.01KD2104A)the German Cancer Aid(grant no.70114735).
文摘Based on intriguing findings from observational studies[1,2],colonoscopy has since long been recommended for colorectal cancer(CRC)screening,long before evidence on its effectiveness in reducing CRC incidence and mortality was demonstrated by a randomized controlled trial(RCT).Such evidence has only recently been provided by the Nordic-European Initiative on Colorectal Cancer(NordICC)trial[3].In this RCT,the risk of CRC was lower among those invited to undergo screening colonoscopy than among those not invited to screening.However,reported CRC risk reduction was smaller than anticipated:The authors derived risk ratios of 0.82(95%confidence interval[CI]=0.70-0.93)and 0.69(95%CI=0.55-0.83)in intention-to-screen analysis and adjusted per-protocol analysis,respectively,suggesting an 18%risk reduction of CRC among those invited for screening and a 31%risk reduction among screening attenders.
基金funded by the Else Kröner Fresenius-Stiftung(2019_A149 and 2022_EKMS.26 to J.C.F.)the Deutsche Forschungsgemeinschaft(DFG,German Research Foundation)-Projektnummer 360372040-SFB 1335(to F.B.,H.P.,S.H.,and K.S.)+12 种基金Projektnummer 395357507-SFB 1371(P04 to D.H.B.and E.H.,P05 to H.P.,P11 to M.T.and J.C.F.,Z02 to K.S.,seed funding to E.T.O.)Projektnummer 324392634-TRR 221(to H.P.,E.H.,M.B-H.,M.R.,M.F.,P.H.,M.E.,D.W.,and W.H.)Projektnummer BA 2851/6-1(to F.B.)Projektnummer PO 1575/5-1(to H.P.)Projektnummer 509149993-TRR 374(to E.V.,M.B-H.)Bavarian Cancer Research Centre(BZFK,to H.P.,W.H.,and F.B.)the German Cancer Aid(70114547 to H.P.,70113964 to J.C.F.)the Wilhelm Sander Foundation(2023.072.1 to J.C.F.,2021.041.1 to S.H.,2021.040.1 to H.P.)the European Hematology Association(to H.P.)a Mechtild Harf Research Grant from the DKMS Foundation for Giving Life(to H.P.)a Young Investigator Award by the Melanoma Research Alliance(to S.H.)the German JoséCarreras leukemia foundation(DJCLS 07 R/2020 to S.H.)funded/co-funded by the European Union(project MICROBOTS,Grant No.101124680 to H.P.).
文摘Intestinal stem cells(ISCs)promote tissue repair after genotoxic or immune-mediated injury.However,ISCs are particularly sensitive to various stressors and primary targets of overwhelming immune responses,such as interferonγ(IFNγ)-mediated killing.In mouse models of radiation therapy-induced gut damage and in biopsies from patients who underwent allogeneic hematopoietic stem cell transplantation,we observed IFNγexpression by intestinal Treg cells.Treg cells leverage combined IFNγand interleukin 10(IL-10)stimulation of ISCs to nurture the growth of intestinal organoids through the activation of the mTORC1 and Myc pathways.Similarly,Treg cells or the combined addition of recombinant IFNγand IL-10 promoted the regeneration of organoids after irradiation,and both cytokines were essential for ensuring epithelial regeneration following acute intestinal tissue injury in vivo.The exposure of organoids to growth factor-free culture conditions revealed distinct EGF-like properties of IFNγand Wnt-like properties of IL-10.While IFNγrapidly induced epithelial proliferation,it depleted the pool of ISCs in vitro.Only the combination of IFNγand IL10 led to epithelial proliferation and organoid growth while simultaneously ensuring ISC maintenance over time.Our results reveal a context-dependent role of inflammatory signaling in ISCs,through which Treg cells promote epithelial repair following therapyinduced injury.
基金supported by grants from Deutsche Kreb-shilfe(70116875)the German Cancer Consortium(DKTK,Heidelberg).
文摘Ovarian cancer,particularly high-grade serous ovariancancer(HGSOC),remains the most lethal gynecologicalmalignancy,with a 5-year survival rate of around 40%due to late diagnosis,recurrence,and the developmentof chemoresistance[1,2].Mutations in tumor protein 53(TP53)occur in over 96%of HGSOC cases,impairing itstumor-suppressive functions,including cell cycle control,DNA repair,and apoptosis.Mutant TP53 promotes tumorprogression,genomic instability,and resistance to stan-dard therapies,thereby worsening patient outcomes[3,4].Death-associated protein kinase 1(DAPK1)is a key reg-ulator of apoptosis and autophagy[5,6].
基金funded by institutional funds from the Georg-Speyer-Haus,the LOEWE Center Frankfurt Cancer Institute(FCl)funded by the Hessen State Ministry for Higher Education,Research and the Arts,as well as grants from the Deutsche Forschungsgemeinschaft(FOR2438:Gr1916/11-1,SFB1292-Project ID:318346496-TP16,SFB1479-Project ID:441891347-P02,GRK2336)the German Federal Ministry of Education and Research(BMBF+1 种基金01KD2206Q/SATURN3)the European Research Council(Advanced Grant PLASTICAN-101021078).
文摘In a recent publication in Cell,Hsu and colleagues describe a novel kind of extracellular vesicle that is involved in the resolution of inflammation.Such large_ageing_neutrophil-derived,vesicles(LAND-Vs)that express CD55^(+) and CD47^(+) are protected against efferocytosis and exhibit anti-inflammatory functions by inhibiting the complement activation.These findings reveal an important functional switch of neutrophils throughout the course of inflammation and identify a novel class of EVs that mediate neutrophil action beyond their limited lifespan,which may open new modes of therapeutic interference in various inflammatory conditions.
基金support from the Open Access Publication Fund of the University of Duisburg-Essensupported by the Deutsche Forschungsgemeinschaft(DFG/JA-2461/7-1)+1 种基金CRC TRR332 project A05 to JJthe Stiftung Tumorforschung Kopf-Hals to CK.
文摘Neutrophils have emerged as key players in tumor progression and are often associated with poor prognosis.Despite ongoing efforts to target neutrophil functions in cancer,therapeutic success has been limited.In this study,we addressed the possibility of blocking STAT3 signaling in neutrophils as a targeted therapeutic intervention in cancer.Conditional deletion of Stat3 in a neutrophil-specific manner(Ly6GcreStat3fl/fl mice)significantly impaired tumor growth and metastasis in mice.Neutrophils isolated from these mice exhibited a strong antitumoral phenotype,with increased MHCII,CD80/86 and ICAM-1 expression.Immune profiling of tumors and tumor-draining lymph nodes of these mice revealed significant enrichment of CD8^(+)T cells(granzymeB^(hi),perforin^(hi) and IFN-γ^(hi))with strong cytotoxic activity.To further translate these findings to human settings,we blocked STAT3 signaling in cancer patient neutrophils via the small molecule in^(hi)bitor LLL12 and assessed its effects on patient-derived tumor explants.In agreement with the in vivo mouse data,we observed the expansion and activation of cytotoxic CD8^(+)T cells in such explants.To test the therapeutic applicability of STAT3 targeting,we utilized myeloid cell-selective STAT3 antisense oligonucleotide(CpG-STAT3ASO)to target neutrophils in vivo in tumor-bearing mice.Consistent with previous results,neutrophil-specific STAT3 knockdown impaired tumor growth and enhanced cytotoxic T cell activity in the tumors and tumor-draining lymph nodes of treated mice.These findings highlight STAT3 signaling as a deleterious pathway supporting the protumoral activity of neutrophils and suggest that neutrophil-targeted STAT3 in^(hi)bition is a promising opportunity for cancer immunotherapy,providing novel insights into targeted therapeutic avenues.
基金supported by the Deutsche Forschungsgemeinschaft(DFG,grant number:KO5055-2-1,KO5055/3-1 to S.K.)the European Research Council(Starting Grant 756017,PoC Grant 101100460,CoG 101124203)the Bruno and Helene Jöster Foundation(360°CAR).Figures were created in BioRender.G.,K.(2025)https://BioRender.com/695n975.
文摘A recent publication by Geraghty et al.in Cell investigates how chimeric antigen receptor(CAR)T cell therapy can induce cognitive impairment in murine models of both central nervous system(CNS)-and non-CNS-based tumors.1 The authors identified persistent neuroinflammation as a key mechanism underlying these cognitive deficits and successfully explored novel therapeutic strategies,including microglial depletion and CCR3 blockade(Fig.1).1.
基金supported by the German Cancer Consortium(DKTK)Deutsche Krebshilfe(DKH#70115743)+1 种基金Deutsche Forschungsgemeinschaft(DFG SA 1374/8-1,Project-ID 515991405 to D.S.DFG SA 1374/7-1,Project-ID 515571394 to D.S.DGF SCHO 1732/2-1,Project-ID 360394750 to D.S.DFG SA 1374/6-1,Project ID 458890590 to D.S.DFG SA 1374/4-3,Project ID 219542602 to D.S.SFB 1321 Project-ID 329628492 to D.S.)the Wilhelm Sander-Stiftung(2020.174.1 and 2017.091.2 to D.S.).
文摘In their recently published study in Science,Popow and colleagues developed a proteolysis-targeting chimera(PROTAC)for the in vivo degradation of several oncogenic KRAS variants^(1).Leveraging detailed biophysical analyses and crystal structures of ternary complexes of candidate ligands for KRAS and the von Hippei-Lindau(VHL)E3 ubiquitin ligase complex,they designed a small molecule capable of potently and selectively targeting 13 of the 17 most common KRAS mutants.
基金supported by The Brain Tumour Charity(grant number GN-000707)supported by DKTK JF Upgrade Next Gen LOGGIC(B310-JF-LOGGIC-MDE)supported by the DFG through a Heisenberg professorship(BR 3662/5-1)and SFB-1479 Oncoescape-Project ID:441891347(P14)。
文摘Pilocytic astrocytomas(PA),the most common pediatric low-grade gliomas(pLGGs),are characterized by genetic MAPK pathway alterations leading to constitutive activation and oncogene-induced senescence(OIS)accompanied with the senescence-associated secretory phenotype(SASP).This study investigates the molecular mechanisms of signaling pathways regulating OIS and SASP in pLGGs using a multi-omics approach.We utilized senescent DKFZ-BT66 cells derived from a primary KIAA1549::BRAF-fusion positive PA to generate RNA-sequencing and phospho-/proteomic datasets before and after treatment with the MEK inhibitor trametinib.Multi-omics factor analysis(MEFISTO)and single sample gene set enrichment analysis(ssGSEA)were employed to identify key OIS effectors and differentially regulated pathways upon MAPK inhibition.Trametinib treatment inhibited MAPK activity,OIS and SASP signatures across all omics levels,functionally underscored by reduced sensitivity towards senolytic drugs.We constructed a pathway network using a prior knowledge approach,mapping n=106 upregulated and n=84 downregulated direct downstream effectors of MAPK leading to OIS/SASP.These effectors are associated with better progression-free survival in pLGG patients,independent of tumor site,level of resection,and genetic aberration.Several compounds targeting signaling nodes(SOD-1,IRS1,CDK1/2,CK2)involved in OIS and under MAPK control were identified,of which n=4 were validated in an additional primary KIAA1549::BRAF fusion pLGG model as potential new therapeutic vulnerabilities for the treatment of pLGG.Our unbiased multiomics signaling pathway analysis identifies a specific and comprehensive network of MAPK-OIS-SASP interdependencies in pLGGs and suggests new therapeutic strategies for these tumors.
基金supported in part by the Outsmarting Osteosarcoma Hero Award(Because of Sydney)the UCLA Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research Rose Hill Foundation Innovator Award+23 种基金supported by NCI R01CA201035,R01CA240711,R01CA229893DoD W81XWH-18-1-0223UCLA SPORE in Prostate Cancer(P50 CA092131)JCCC Cancer support grant from NIH P30 CA016042(PI:Teitell)Knut and Alice Wallenberg FoundationBertha Kamprad FoundationDavid H.Koch Prostate Cancer Foundation Young Investigator AwardSwedish Research CouncilSwedish Cancer SocietySIPEA FoundationSwedish Childhood Cancer FoundationJohn and Augusta Perssons FoundationRoyal Physiographic Society of LundFranke and Margareta Bergqvist FoundationCrafoord FoundationLund University Medical Faculty research time allocation award,IngaBrittArne Lundberg Research Foundation,the German Research Foundation(552440240)the German Cancer Consortium(DKTK)the German Federal Ministry of Education and Research(BMBFgrant no.01KD2206A/SATURN3)funding support from the Children’s Discovery Institute of the St.Louis Children’s Hospital.Confocal laser scanning microscopy was performed at the Advanced Light Microscopy/Spectroscopy Laboratory(RRID:SCR_022789)the Leica Microsystems Center of Excellence at the California NanoSystems Institute at UCLA with funding support from NIH Shared Instrumentation Grant S10OD025017Flow cytometry was performed in the UCLA Jonsson Comprehensive Cancer Center(JCCC)Center for AIDS Research Flow Cytometry Core Facility that is supported by National Institutes of Health awards P30 CA016042 and 5P30 AI028697。
文摘Leucine-rich repeat containing 15(LRRC15)has emerged as an attractive biomarker and target for cancer therapy.Transforming growth factor-β(TGFβ)induces the expression of this plasma membrane protein specifically in aggressive and treatment resistant tumor cells derived from mesenchymal stem cells,with minimal expression observed in non-neoplastic tissues.We have developed a humanized monoclonal antibody,DUNP19,that specifically binds with high affinity to a phylogenetically conserved LRRC15 epitope and is rapidly internalized upon LRRC15 binding.In multiple subcutaneous and orthotopic tumor xenograft mouse models,Lutetium-177 labeled DUNP19([^(177)Lu]Lu-DUNP19)enabled non-invasive imaging and molecularly precise radiotherapy to LRRC15-expressing cancer cells and murine cancer-associated fibroblasts,effectively halting tumor progression and prolonging survival with minimal toxicity.Transcriptomic analyses of[^(177)Lu]Lu-DUNP19-treated tumors reveal a loss of pro-tumorigenic mechanisms,including a previously reported TGF β-induced LRRC15+signature associated with immunotherapy resistance.In a syngeneic tumor model,administration of[^(177)Lu]Lu-DUNP19 significantly potentiated checkpoint-blockade therapy,yielding durable complete responses.Together,these results demonstrate that radio-theranostic targeting of LRRC15 with DUNP19 is a compelling precision medicine platform for image-guided diagnosis,eradication,and reprogramming of LRRC15+tumor tissue that drives immunoresistance and disease aggressiveness in a wide range of currently untreatable malignancies.
基金supported by the Deutsche Forschungsgemeinschaft(DFG)(German Research Foundation,grant numbers:KU 1320/10-1 and HO 6586/1-1,and SFB1430,project 424228829)the Sachsische Aufbaubank(grant number:10071450).
文摘Immunotherapy is currently one of the most promising treatment options for malignant melanoma[1].To uncover new immunological targets for future treatment approaches,single-cell transcriptomic and epigenomic analyses were performed on human primary melanoma(MM)and melanocytic nevus(Nev)samples(Figure 1A).
基金supported by Marga and Walter Boll Stiftung,Deutsche Forschungsgemeinschaft(BR2278/8-1,HU 2795/2-1)TransRegio 332(project A4)Deutsche Krebshilfe and COST Action Mye-Infobank,supported by COST(European Cooperation in Science and Technology).
文摘In the tumor host,neutrophils may exhibit protumor or antitumor activity.It is hypothesized that in response to host-derived or therapy-induced factors,neutrophils adopt diverse functional states to ultimately execute these differential functions.Here,we provide an alternative scenario in which the response of an individual tumor cell population determines the overall protumor versus antitumor outcome of neutrophil‒tumor interactions.Experimentally,we show that human neutrophils,which are sequentially stimulated with bacteria and secreted factors from tumor cells,kill a certain proportion of tumor target cells.However,the majority of the tumor cells remained resistant to this neutrophil-mediated killing and underwent a functional,phenotypic and transcriptomic switch that was reminiscent of partial epithelial‒to-mesenchymal transition.This cell biological switch was associated with physical escape from NK-mediated killing and resulted in enhanced metastasis to the lymph nodes in a preclinical orthotopic mouse model.Mechanistically,we identified the antimicrobial neutrophil granule proteins neutrophil elastase(NE)and matrix metalloprotease-9(MMP-9)as the molecular mediators of this functional switch.We validated these data in patients with head and neck cancer and identified bacterially colonized intratumoral niches that were enriched for mesenchymal tumor cells and neutrophils expressing NE and MMP-9.Our data reveal the parallel execution of tumor cytotoxic and prometastatic activity by activated neutrophils and identify NE and MMP-9 as mediators of lymph node metastasis.The identified mechanism explains the functional dichotomy of tumor-associated neutrophils at the level of the tumor target cell response and has implications for superinfected cancers and the dysbiotic tumor microenvironment.
