A novel coronavirus known as severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)has spread across the world,prompting the World Health Organization to declare the coronavirus disease of 2019(COVID-19)a public ...A novel coronavirus known as severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)has spread across the world,prompting the World Health Organization to declare the coronavirus disease of 2019(COVID-19)a public health emergency of international concern.Cancer patients are regarded as a highly vulnerable population to SARS-CoV-2 infection and development of more severe COVID-19 symptoms,which is possibly due to the systemic immunosuppressive state caused directly by tumor growth and indirectly by effects of anticancer treatment.Currently,much effort has been directed toward studying the pathogenesis and treatment of COVID-19,but the risk profiles,prognoses,and treatment outcomes in cancer patients remain unclear.Based on the current literature,we summarize the risk profiles,clinical and biochemical characteristics,and therapy outcomes of COVID-19 infections in cancer patients.The challenges in the clinical care of cancer patients with COVID-19 are discussed.The goal of this review is to stimulate research to better understand the biological impact and prognoses of COVID-19 infections in cancer patients,thus facilitating improvement of the clinical management of these patients.展开更多
Neutrophils are innate immune cells that function predominantly against pathogens,while recent studies have revealed additional crucial roles in various diseases,including cancers[1–3].For instance,neutrophils expres...Neutrophils are innate immune cells that function predominantly against pathogens,while recent studies have revealed additional crucial roles in various diseases,including cancers[1–3].For instance,neutrophils expressing the co-inhibitory molecule programmed death-ligand 1(PD-L1)were identified as novel immunosuppressive myeloid cells that impair cytotoxic T cell(CTL)activity via programmed cell death protein 1(PD-1)/PD-L1 interaction[4,5].Although some stimuli have been identified,it is still unclear whether the nucleic acid sensing system(NAS)participates in PD-L1 upregulation in neutrophils[6].Here,we report that increased cell-free nucleic acid(CFNA)upregulates PD-L1 expression via intracellular Toll-like receptor(TLR)activation in neutrophils following tumor expansion.展开更多
Background:Tumor metastasis is a major threat to cancer patient survival.The organ-specific niche plays a pivotal role in tumor organotropic metas-tasis.Fibroblasts serve as a vital component of the metastatic microen...Background:Tumor metastasis is a major threat to cancer patient survival.The organ-specific niche plays a pivotal role in tumor organotropic metas-tasis.Fibroblasts serve as a vital component of the metastatic microenviron-ment,but how heterogeneous metastasis-associated fibroblasts(MAFs)promote organotropic metastasis is poorly characterized.Here,we aimed to decipher the heterogeneity of MAFs and elucidate the distinct roles of these fibroblasts in pulmonary metastasis formation in breast cancer.Methods:Mouse models of breast cancer pulmonary metastasis were estab-lished using an in vivo selection method of repeated injections of metastatic cells purified from the mouse lung.Single-cell RNA-sequencing(scRNA-seq)was employed to investigate the heterogeneity of MAFs.Transgenic mice were used to examine the contribution of tryptophan 2,3-dioxygenase-positive matrix fibroblasts(TDO2^(+)MFs)in lung metastasis.Results:We uncovered 3 subtypes of MAFs in the lung metastatic microenviron-ment,and their transcriptome profiles changed dynamically as lung metastasis evolved.As the predominant subtype,MFs were exclusively marked by platelet-derived growth factor receptor alpha(PDGFRA)and mainly located on the edge of the metastasis,and T cells were enriched around MFs.Notably,high MF sig-natures were significantly associated with poor survival in breast cancer patients.Lung metastases were markedly diminished,and the suppression of T cells was dramatically attenuated in MF-depleted experimental metastatic mouse mod-els.We found that TDO2^(+)MFs controlled pulmonary metastasis by producing kynurenine(KYN),which upregulated ferritin heavy chain 1(FTH1)level in dis-seminated tumor cells(DTCs),enabling DTCs to resist ferroptosis.Moreover,TDO2^(+)MF-secreted chemokines C-C motif chemokine ligand 8(CCL8)and C-C motif chemokine ligand 11(CCL11)recruited T cells.TDO2^(+)MF-derived KYN induced T cell dysfunction.Conditional knockout of Tdo2 in MFs diminished lung metastasis and enhanced immune activation.Conclusions:Our study reveals crucial roles of TDO2^(+)MFs in promoting lung metastasis and DTCs’immune evasion in the metastatic niche.It suggests that targeting the metabolism of lung-specific stromal cells may be an effective treatment strategy for breast cancer patients with lung metastasis.展开更多
基金supported by the National Institutes of Health(Grant No.2R01CA151610)Department of Defense(Grant No.W81XWH-18-1-0067)a Samuel Oschin Cancer Institute Discovery Fund Award and Community Outreach and Engagement Developmental Fund Award.
文摘A novel coronavirus known as severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)has spread across the world,prompting the World Health Organization to declare the coronavirus disease of 2019(COVID-19)a public health emergency of international concern.Cancer patients are regarded as a highly vulnerable population to SARS-CoV-2 infection and development of more severe COVID-19 symptoms,which is possibly due to the systemic immunosuppressive state caused directly by tumor growth and indirectly by effects of anticancer treatment.Currently,much effort has been directed toward studying the pathogenesis and treatment of COVID-19,but the risk profiles,prognoses,and treatment outcomes in cancer patients remain unclear.Based on the current literature,we summarize the risk profiles,clinical and biochemical characteristics,and therapy outcomes of COVID-19 infections in cancer patients.The challenges in the clinical care of cancer patients with COVID-19 are discussed.The goal of this review is to stimulate research to better understand the biological impact and prognoses of COVID-19 infections in cancer patients,thus facilitating improvement of the clinical management of these patients.
基金supported by the National Institutes of Health grants(R01AI164519,2R01CA151610,R21CA280458)American Heart Association’s Career Development award(23CDA1052548)U.S.Department of Defense(W81XWH-18-1-0067)and the Glazer Foundation.
文摘Neutrophils are innate immune cells that function predominantly against pathogens,while recent studies have revealed additional crucial roles in various diseases,including cancers[1–3].For instance,neutrophils expressing the co-inhibitory molecule programmed death-ligand 1(PD-L1)were identified as novel immunosuppressive myeloid cells that impair cytotoxic T cell(CTL)activity via programmed cell death protein 1(PD-1)/PD-L1 interaction[4,5].Although some stimuli have been identified,it is still unclear whether the nucleic acid sensing system(NAS)participates in PD-L1 upregulation in neutrophils[6].Here,we report that increased cell-free nucleic acid(CFNA)upregulates PD-L1 expression via intracellular Toll-like receptor(TLR)activation in neutrophils following tumor expansion.
基金supported by National Key Projects of Ministry of Science and Technology of China(MOST 2018YFE0113700)National Natural Science Foundation of China(NSFC82173155,NSFC81874199)+2 种基金the Outstanding Professorship Program of Chongqing Medical University(2019-R10005)to Manran Liusupported by the Outstanding Postgraduate Fund of Chongqing Medical University(BJRC202021,BJRC202025)the Chongqing Graduate Research and Innovation Project of the Chongqing Education Committee(CYB22218)for Shanchun Chen.
文摘Background:Tumor metastasis is a major threat to cancer patient survival.The organ-specific niche plays a pivotal role in tumor organotropic metas-tasis.Fibroblasts serve as a vital component of the metastatic microenviron-ment,but how heterogeneous metastasis-associated fibroblasts(MAFs)promote organotropic metastasis is poorly characterized.Here,we aimed to decipher the heterogeneity of MAFs and elucidate the distinct roles of these fibroblasts in pulmonary metastasis formation in breast cancer.Methods:Mouse models of breast cancer pulmonary metastasis were estab-lished using an in vivo selection method of repeated injections of metastatic cells purified from the mouse lung.Single-cell RNA-sequencing(scRNA-seq)was employed to investigate the heterogeneity of MAFs.Transgenic mice were used to examine the contribution of tryptophan 2,3-dioxygenase-positive matrix fibroblasts(TDO2^(+)MFs)in lung metastasis.Results:We uncovered 3 subtypes of MAFs in the lung metastatic microenviron-ment,and their transcriptome profiles changed dynamically as lung metastasis evolved.As the predominant subtype,MFs were exclusively marked by platelet-derived growth factor receptor alpha(PDGFRA)and mainly located on the edge of the metastasis,and T cells were enriched around MFs.Notably,high MF sig-natures were significantly associated with poor survival in breast cancer patients.Lung metastases were markedly diminished,and the suppression of T cells was dramatically attenuated in MF-depleted experimental metastatic mouse mod-els.We found that TDO2^(+)MFs controlled pulmonary metastasis by producing kynurenine(KYN),which upregulated ferritin heavy chain 1(FTH1)level in dis-seminated tumor cells(DTCs),enabling DTCs to resist ferroptosis.Moreover,TDO2^(+)MF-secreted chemokines C-C motif chemokine ligand 8(CCL8)and C-C motif chemokine ligand 11(CCL11)recruited T cells.TDO2^(+)MF-derived KYN induced T cell dysfunction.Conditional knockout of Tdo2 in MFs diminished lung metastasis and enhanced immune activation.Conclusions:Our study reveals crucial roles of TDO2^(+)MFs in promoting lung metastasis and DTCs’immune evasion in the metastatic niche.It suggests that targeting the metabolism of lung-specific stromal cells may be an effective treatment strategy for breast cancer patients with lung metastasis.
