Dr. Su’s Group Demonstrates that Complement Signals Determine Opposite Effects of B Cells in Tumors
Source：Shicheng Su
2020-06-15
Immunotherapy that targets the tumor microenvironment (TME) has revolutionized oncological treatments. It has been well documented that B cells, one of the most important immune cells in the TME, plays an important role in promoting tumor progression. However, recent clinical trials demonstrated that B cell infiltration is closely associated with improved response to immunotherapy, suggesting tumor-associated B cells exhibit high heterogeneity and plasticity. However, its underlying mechanisms remained elusive.
Dr. Shicheng Su’s group from Sun Yat-Sen Memorial Hospital shows that complement signals initiated by immunogenic tumor cell death foster a previously unidentified B cell subset, which enhances the anti-tumor immune response by ICOSL. This finding help us to better understand how innate immune signals dictate heterogeneity of adaptive immune cells, and provide implications for designing novel anti-cancer therapy. In March 5th, the article “Complement Signals Determine Opposite Effects of B Cells in Chemotherapy-Induced Immunity” was published in Cell Journal. This study is highlighted by a number of journals, including Cell, Nature Immunology Review, Nature Reviews Clinical Oncology and Cancer Discovery.
They isolated B cells from paired breast cancer tissues of patients before and after neo-adjuvant chemotherapy. Using single-cell sequencing, they found that a subset of B cells with an ICOSL+CR2highIL-10-CD20+CD38+CD27+IgA-IgD- phenotype emerges after chemotherapy. Using an Automated Image Analysis with Background Subtraction (AIABS) system, they revealed that ICOSL+ B cells accumulate in tertiary lymphoid organs (TLOs) and have significantly closer contact with T cells compared to ICOSL- B cells. Using the B-cell-specific ICOSL knockout mice, they discovered that conditional knockout of ICOSL in B cells dramatically undermines the chemotherapy effects. Given that ICOSL+ B cells exhibited elevated CR2 levels, they elucidated the role of complement signals in B cells after chemotherapy. They generated the B-cell-specific CR2 knockout mice and found that the upregulation of ICOSL after chemotherapy is absent in CR2-deficient B cells. To investigate the opposite role of B cells in different tumor model, they used multiple breast cancer cell lines in vitro and transgenic adenocarcinoma of the mouse prostate (TRAMP-C2) model in vivo and found that CD55, a complement inhibitory protein, is significantly lower in tumor cells that could induce ICOSL+ B cells after chemotherapy than in those that could not.
Altogether, the study suggested that ICOSL induced in tumor-infiltrating B cells after chemotherapy elicits the anti-tumor T cell immune response and improves chemotherapy efficacy. Complement activation in the TME exposed to chemotherapy is responsible for inducing ICOSL+ B cells via CR2, and CD55 expression in tumor cells determines the opposite role of B cells in anti-tumor immunity and chemotherapy efficacy.
Dr. Yiwen Lu, Dr. Qiyi Zhao, and Dr. Jian-You Liao are co-first authors. Academician Erwei Song provides valuable advice for this project. This work is supported by grants from the National Key Research and Development Program of China, the Natural Science Foundation of China.
Hyperlink of the article: https://doi.org/10.1016/j.cell.2020.02.015
Hyperlink of related reports:
https://doi.org/10.1016/j.cell.2020.02.046
https://doi.org/10.1038/s41577-020-0294-5
https://doi.org/10.1038/s41571-020-0376-0
https://doi.org/10.1158/2159-8290.CD-RW2020-039
Dr. Shicheng Su’s group from Sun Yat-Sen Memorial Hospital shows that complement signals initiated by immunogenic tumor cell death foster a previously unidentified B cell subset, which enhances the anti-tumor immune response by ICOSL. This finding help us to better understand how innate immune signals dictate heterogeneity of adaptive immune cells, and provide implications for designing novel anti-cancer therapy. In March 5th, the article “Complement Signals Determine Opposite Effects of B Cells in Chemotherapy-Induced Immunity” was published in Cell Journal. This study is highlighted by a number of journals, including Cell, Nature Immunology Review, Nature Reviews Clinical Oncology and Cancer Discovery.
They isolated B cells from paired breast cancer tissues of patients before and after neo-adjuvant chemotherapy. Using single-cell sequencing, they found that a subset of B cells with an ICOSL+CR2highIL-10-CD20+CD38+CD27+IgA-IgD- phenotype emerges after chemotherapy. Using an Automated Image Analysis with Background Subtraction (AIABS) system, they revealed that ICOSL+ B cells accumulate in tertiary lymphoid organs (TLOs) and have significantly closer contact with T cells compared to ICOSL- B cells. Using the B-cell-specific ICOSL knockout mice, they discovered that conditional knockout of ICOSL in B cells dramatically undermines the chemotherapy effects. Given that ICOSL+ B cells exhibited elevated CR2 levels, they elucidated the role of complement signals in B cells after chemotherapy. They generated the B-cell-specific CR2 knockout mice and found that the upregulation of ICOSL after chemotherapy is absent in CR2-deficient B cells. To investigate the opposite role of B cells in different tumor model, they used multiple breast cancer cell lines in vitro and transgenic adenocarcinoma of the mouse prostate (TRAMP-C2) model in vivo and found that CD55, a complement inhibitory protein, is significantly lower in tumor cells that could induce ICOSL+ B cells after chemotherapy than in those that could not.
Altogether, the study suggested that ICOSL induced in tumor-infiltrating B cells after chemotherapy elicits the anti-tumor T cell immune response and improves chemotherapy efficacy. Complement activation in the TME exposed to chemotherapy is responsible for inducing ICOSL+ B cells via CR2, and CD55 expression in tumor cells determines the opposite role of B cells in anti-tumor immunity and chemotherapy efficacy.
Dr. Yiwen Lu, Dr. Qiyi Zhao, and Dr. Jian-You Liao are co-first authors. Academician Erwei Song provides valuable advice for this project. This work is supported by grants from the National Key Research and Development Program of China, the Natural Science Foundation of China.
Hyperlink of the article: https://doi.org/10.1016/j.cell.2020.02.015
Hyperlink of related reports:
https://doi.org/10.1016/j.cell.2020.02.046
https://doi.org/10.1038/s41577-020-0294-5
https://doi.org/10.1038/s41571-020-0376-0
https://doi.org/10.1158/2159-8290.CD-RW2020-039
