Surgery is essential for controlling the symptoms and complications of stage IV breast cancer.However,locoregional treatment of primary tumors often results in distant progression,including lung metastasis,the most co...Surgery is essential for controlling the symptoms and complications of stage IV breast cancer.However,locoregional treatment of primary tumors often results in distant progression,including lung metastasis,the most common type of visceral metastasis.As a minimally invasive thermal therapy,microwave ablation(MWA)has been attempted in the treatment of breast cancer,but the innate immune response after MWA has not yet been reported.Using two murine models of stage IV breast cancer,we found that MWA of primary breast cancer inhibited the progression of lung metastasis and improved survival.NK cells were activated after MWA of the primary tumor and exhibited enhanced cytotoxic functions,and the cytotoxic pathways of NK cells were activated.Depletion experiments showed that NK cells but not CD4+or CD8+T cells played a pivotal role in prolonging survival.Then,we found that compared with surgery or control treatment,MWA of the primary tumor induced completely different NK-cell-related cytokine profiles.Macrophages were activated after MWA of the primary tumor and produced IL-15 that activated NK cells to inhibit the progression of metastasis.In addition,MWA of human breast cancer stimulated an autologous NK-cell response.These results demonstrate that MWA of the primary tumor in metastatic breast cancer inhibits metastatic progression via the macrophage/IL-15/NK-cell axis.MWA of the primary tumor may be a promising treatment strategy for de novo stage IV breast cancer,although further substantiation is essential for clinical testing.展开更多
Metastasis is the major cause of cancer-related death,and lymph node is the most common site of metastasis in breast cancer.However,the alterations that happen in tumor-draining lymph nodes(TDLNs)to form a premetastat...Metastasis is the major cause of cancer-related death,and lymph node is the most common site of metastasis in breast cancer.However,the alterations that happen in tumor-draining lymph nodes(TDLNs)to form a premetastatic microenvironment are largely unknown.Here,we first report the dynamic changes in size and immune status of TDLNs before metastasis in breast cancer.With the progression of tumor,the TDLN is first enlarged and immune-activated at early stage that contains specific antitumor immunity against metastasis.The TDLN is then contracted and immunosuppressed at late stage before finally getting metastasized.Mechanistically,B and follicular helper T(Tfh)cells parallelly expand and contract to determine the size of TDLN.The activation status and specific antitumor immunity of CD8+T cells in the TDLN are determined by interleukin-21(IL-21)produced by Tfh cells,thus showing parallel changes.The turn from activated enlargement to suppressed contraction is due to the spontaneous contraction of germinal centers mediated by follicular regulatory T cells.On the basis of the B-Tfh-IL-21-CD8^(+)T cell axis,we prove that targeting the axis could activate TDLNs to resist metastasis.Together,our findings identify the dynamic alterations and regulatory mechanisms of premetastatic TDLNs of breast cancer and provide new strategies to inhibit lymph node metastasis.展开更多
B cells are generated in the bone marrow during ontogeny and migrate to peripheral lymphoid organs,where they encounter antigens to elicit humoral immunity.During the past decade,many novel B-cell subsets with distinc...B cells are generated in the bone marrow during ontogeny and migrate to peripheral lymphoid organs,where they encounter antigens to elicit humoral immunity.During the past decade,many novel B-cell subsets with distinct phenotypes and functions have been identified,and among these subsets,age-associated B cells(ABCs)were first characterized as a B-cell subset that accumulates with age[1].展开更多
基金This work was supported in part by the National Natural Science Foundation of China(81771953)the Six Kinds of Outstanding Talent Foundation of Jiangsu Province(WSW-014,to W.Z.)+1 种基金the Natural Science Foundation of Jiangsu Province(BK20180108)a project funded by the Priority Academic Program Development of Jiangsu Higher Education Institutions(PAPD).
文摘Surgery is essential for controlling the symptoms and complications of stage IV breast cancer.However,locoregional treatment of primary tumors often results in distant progression,including lung metastasis,the most common type of visceral metastasis.As a minimally invasive thermal therapy,microwave ablation(MWA)has been attempted in the treatment of breast cancer,but the innate immune response after MWA has not yet been reported.Using two murine models of stage IV breast cancer,we found that MWA of primary breast cancer inhibited the progression of lung metastasis and improved survival.NK cells were activated after MWA of the primary tumor and exhibited enhanced cytotoxic functions,and the cytotoxic pathways of NK cells were activated.Depletion experiments showed that NK cells but not CD4+or CD8+T cells played a pivotal role in prolonging survival.Then,we found that compared with surgery or control treatment,MWA of the primary tumor induced completely different NK-cell-related cytokine profiles.Macrophages were activated after MWA of the primary tumor and produced IL-15 that activated NK cells to inhibit the progression of metastasis.In addition,MWA of human breast cancer stimulated an autologous NK-cell response.These results demonstrate that MWA of the primary tumor in metastatic breast cancer inhibits metastatic progression via the macrophage/IL-15/NK-cell axis.MWA of the primary tumor may be a promising treatment strategy for de novo stage IV breast cancer,although further substantiation is essential for clinical testing.
基金supported in part by the National Natural Science Foundation of China(81771953 and 82172683)a project funded by Jiangsu Provincial Science and Technology Department(BE2022807).
文摘Metastasis is the major cause of cancer-related death,and lymph node is the most common site of metastasis in breast cancer.However,the alterations that happen in tumor-draining lymph nodes(TDLNs)to form a premetastatic microenvironment are largely unknown.Here,we first report the dynamic changes in size and immune status of TDLNs before metastasis in breast cancer.With the progression of tumor,the TDLN is first enlarged and immune-activated at early stage that contains specific antitumor immunity against metastasis.The TDLN is then contracted and immunosuppressed at late stage before finally getting metastasized.Mechanistically,B and follicular helper T(Tfh)cells parallelly expand and contract to determine the size of TDLN.The activation status and specific antitumor immunity of CD8+T cells in the TDLN are determined by interleukin-21(IL-21)produced by Tfh cells,thus showing parallel changes.The turn from activated enlargement to suppressed contraction is due to the spontaneous contraction of germinal centers mediated by follicular regulatory T cells.On the basis of the B-Tfh-IL-21-CD8^(+)T cell axis,we prove that targeting the axis could activate TDLNs to resist metastasis.Together,our findings identify the dynamic alterations and regulatory mechanisms of premetastatic TDLNs of breast cancer and provide new strategies to inhibit lymph node metastasis.
基金supported by the National Natural Science Foundation of China(82071817,82171793,82371803)the Shenzhen Science and Technology Program(YCYJ20210324114602008)+2 种基金the Jiangsu Provincial Key Research and Development Program(BE2023758)the Hong Kong Research Grants Council(17113319,17103821)the RGC Theme-based Research Scheme(TRS)(T12-703/19-R)。
文摘B cells are generated in the bone marrow during ontogeny and migrate to peripheral lymphoid organs,where they encounter antigens to elicit humoral immunity.During the past decade,many novel B-cell subsets with distinct phenotypes and functions have been identified,and among these subsets,age-associated B cells(ABCs)were first characterized as a B-cell subset that accumulates with age[1].
