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Clinical experience in cancer immunotherapy reveals that remodeling of the anticancer signature of the tumor microenvironment plays an important role in tumor control
.
Existing immunotherapy mainly focuses on the transformation of immune cells such as CD8+ T cells and NK cells
.
In recent years, studies have revealed that B lymphocytes exhibit inconsistent functions in the occurrence and development of various cancers (breast tumor, melanoma, colorectal cancer, ovarian cancer, etc.
) The precise study of differentiation may unravel the contradictions and provide new ideas for the development of novel and highly effective anticancer therapies
.
Recently, Professor Liu Wanli from the School of Life/Life Center/Institute of Immunology of Tsinghua University and Professor Shen Zhanlong, Chief Physician of Gastrointestinal Surgery of Peking University People's Hospital/Professor of Surgical Oncology Laboratory, published a long research paper An Asian-Specific Variant in Human IgG1 on J Clin Invest.
Represses Colorectal Tumorigenesis by Shaping the Tumor Microenvironment
.
The paper reveals that the single nucleotide polymorphism variant of the IgG1 memory B cell antigen receptor annexed immunoglobulin IgG1 heavy chain gene IGHG1 (referred to as hIgG1-G396R) protects against the occurrence and development of colorectal cancer, and analyzes the IgG1 memory B cells Mechanisms of action and potential applications in remodeling the tumor-anticancer microenvironment
.
Previous research by Prof.
Wanli Liu's group (Chen et al, Science, 2018) found that the hIgG1-G396R variant makes the intracellular tyrosine signal transduction motif of the IgG1 memory B cell antigen receptor and the Src family tyrosine The increased affinity of acid kinase Lyn reduces the immune activation threshold of IgG1 memory B cells, which in turn enhances clonal proliferation and plasma cell differentiation after such memory B cells recognize relevant antigens
.
Based on this, Professor Liu Wanli's research group and Professor Shen Zhanlong's research group worked together to conduct epidemiological analysis on a cohort of more than 1,000 colorectal cancer patients with ten-year follow-up information in the Department of Gastrointestinal Surgery of Peking University People's Hospital, and found that hIgG1-G396R homozygous Genotype tumor patients had significantly improved overall survival (OS, HR=0.
504, P=0.
007) and progression-free survival (PFS, HR=0.
57, P=0.
018).
Further multivariate COX risk analysis revealed that hIgG1- G396R homozygous genotype is an independent protective prognostic survival factor in colorectal cancer patients
.
In order to analyze the molecular mechanism of hIgG1-G396R in resisting the occurrence and development of colorectal cancer, the research group constructed mIgG2c-G400R gene knock-in mice (mIgG2c-G400R-KI mice), and applied tumor cell transplantation models and chemical mutagenesis of inflammatory progenitors.
A colorectal cancer model was further explored in mice, and it was found that colon adenocarcinoma cells MC38 and melanoma cells B16F10 were significantly affected by subcutaneous inoculation of mIgG2c-G400R-KI mice compared with wild-type control mice.
Inhibition; in a chemically mutagenized inflammatory primary colorectal cancer model, mIgG2c-G400R-KI mice also showed significantly reduced pathological phenotypes, including weight loss rate, disease activity index, tumor microenvironment inflammation level, etc.
Colon anatomical analysis at the end point of the primary tumor model further confirmed the presence of fewer and smaller colon tumors in the gut of mIgG2c-G400R-KI mice
.
Immune mechanism exploration found that in these two colon cancer animal models, mIgG2c-G400R-KI mice produced significantly higher levels of tumor-associated antibodies of the IgG2 subtype than WT mice, and had higher levels of IgG2c+ plasma in tumor tissues cell infiltration
.
In order to further study the molecular mechanism of memory B cell antigen receptor activation, the research group further constructed mIgG2c intracellular domain-deficient mice, and then in three different types of memory B cell antigen receptor membrane-linked antibody heavy chain intracellular In mice genetically modified in the signal transduction region, inoculated with tumor cells expressing OVA antigen, subsequent analysis found that there was a significant negative correlation between tumor size and OVA-specific IgG2c titer; more importantly, the spleen and bone marrow of mIgG2c-G400R-KI mice The proportions of germinal center B cells, plasma cells, and memory B cells of OVA-specific IgG2c subtype were significantly up-regulated compared with the other two types of genetically modified mice
.
Consistent with the above results, in the colon cancer model, IgG2c+ plasma cells were significantly increased in the mesenteric lymph nodes and intestinal lamina propria of mIgG2c-G400R-KI mice, and tumor drainage in mIgG2c-G400R-KI mice after MC38 inoculation IgG2c+ memory B cells were also significantly increased in lymph nodes, demonstrating that this variant increases memory B cell differentiation into plasma cells and promotes memory B cell infiltration in draining lymph nodes and the tumor microenvironment
.
Analysis of surgical samples from clinical patients further confirmed that tumor patients with hIgG1-G396R homozygous genotype also had more IgG1+ plasma cells and antibody infiltration in the tumor microenvironment
.
The humoral immunity dominated by B lymphocytes, the cellular immunity dominated by T lymphocytes, and the innate immunity dominated by innate immune cells have always influenced and closely related to each other in the tumor microenvironment
.
In order to further explore the immunological mechanism behind the above results, the research group used a variety of research methods such as flow cytometry and immunohistochemical staining, and found that the tumors of hIgG1-G396R homozygous genotype tumor patients and mIgG2c-G400R-KI mice In the microenvironment, the infiltration level and activation level of cDC1 DC cells and CD8+ T cells were significantly increased, and more importantly, the chemokine transcription level and the area, number and activity of tertiary lymphoid structures in the tumor microenvironment were also significantly increased
.
As a further independent confirmation of the core conclusions of the paper, the single-cell transcriptional analysis of colorectal cancer tumor tissue in collaboration with Professor Zhang Zemin and Dr.
Zhang Lei (now Shenzhen Bay Laboratory Distinguished Researcher) of Peking University found that patients with hIgG1-G396R homozygous genotype IgG+ plasma cells, CXCR5+ follicular helper T cells, CXCR6+ activated helper T cells, CD6+ tumor-resident CD8+ T cells, and CD160+ intraepithelial CD8+ T cells were all up-regulated in the tumor microenvironment of tumor cells, while Treg cells and LAYN+ depleted Sexual CD8+ T cells were characterized by downregulation
.
The aforementioned results demonstrate that hIgG1-G396R not only affects the differentiation of plasma cells and the production of tumor-specific antibodies in tumor tissue, but also enhances the overall anti-tumor immunity in the tumor tissue microenvironment by changing the immune microenvironment of tumor patients
.
In order to further explore how the enhanced antibody response affects the tumor microenvironment, the research group found that G400R mice had higher concentrations of antigen-specific antibodies to enhance the phagocytic ability of phagocytes, and the IgG-coated IgG purified in the serum of G400R mice Tumor cells can enhance the ability of DCs to present antigens to T cells
.
Finally, adoptive transfer of tumor-associated B cells or antibodies derived from mIgG2c-G400R mice showed therapeutic efficacy in a mouse tumor model, explaining the potential clinical implications
.
To sum up, this paper starts from the hIgG1-G396R variant enhancing the immune activation of memory B cells and the differentiation of plasma cells and even the production of IgG1 antibodies, and carries out a clinical correlation analysis of a large clinical cohort of colorectal cancer patients, to a genetically modified mouse model.
Combined with the study of colorectal cancer models, and the analysis of cell infiltration in the tumor microenvironment based on flow cytometry and immunohistochemistry, to the analysis of cell interactions based on laser confocal microscopy, and finally ending with single-cell sequencing studies of clinical samples
.
This series of multidisciplinary cross-type studies show that hIgG1-G396R is one of the protective prognostic factors in patients with colorectal cancer, revealing that hIgG1-G396R has the potential to be used as a prognostic indicator for patients in the field of colorectal cancer.
The guidelines provide reference value, and also suggest that adoptive transfer of IgG1+ B cells may be one of the powerful strategies for cancer immunotherapy, and inspire more researchers to explore the possibility of applying B cells to immunotherapy
.
The results of this series of studies have deepened people's understanding of the function and protective immunological mechanism of memory B cells in colorectal cancer, and made reasonable predictions for the prognostic level and clinicopathological characteristics of patients with clinically different genotypes of colorectal cancer.
It also provides an innovative research model for adoptive transfer of memory B cells to treat cancer
.
Schematic illustration of the IgG1 memory B-cell antigen receptor membrane-linked heavy chain hIgG1-G396R variant remodeling the colorectal cancer tumor microenvironment and enhancing antitumor immunity
.
The left is the control group, and the right is the enhanced anti-tumor immune microenvironment in patients with hIgG1-G396R homozygous genotype tumors: including enhanced TLS structure and function, increased IgG1+ plasma cell differentiation and infiltration, up-regulated IgG1 antibody infiltration, and then Functions through opsonization of antibody constant regions (ADCP, ADC, etc.
)
.
Dr.
Yang Bing has graduated from Liu Wanli's research group, Dr.
Zhang Zhen has graduated from Shen Zhanlong's research group, and Dr.
Chen Xiangjun has graduated from Liu Wanli's research group.
They are the co-first authors of this paper
.
Professor Liu Wanli of Tsinghua University and Professor Shen Zhanlong of Peking University People's Hospital are the co-corresponding authors of the paper
.
Original link: https:// Publisher: 11 Reprint Notice [Non-original article] The copyright of this article belongs to the author of the article, and personal sharing is welcome.
Reprinting is prohibited without permission.
The author owns All legal rights, violators will be prosecuted
.
.
Existing immunotherapy mainly focuses on the transformation of immune cells such as CD8+ T cells and NK cells
.
In recent years, studies have revealed that B lymphocytes exhibit inconsistent functions in the occurrence and development of various cancers (breast tumor, melanoma, colorectal cancer, ovarian cancer, etc.
) The precise study of differentiation may unravel the contradictions and provide new ideas for the development of novel and highly effective anticancer therapies
.
Recently, Professor Liu Wanli from the School of Life/Life Center/Institute of Immunology of Tsinghua University and Professor Shen Zhanlong, Chief Physician of Gastrointestinal Surgery of Peking University People's Hospital/Professor of Surgical Oncology Laboratory, published a long research paper An Asian-Specific Variant in Human IgG1 on J Clin Invest.
Represses Colorectal Tumorigenesis by Shaping the Tumor Microenvironment
.
The paper reveals that the single nucleotide polymorphism variant of the IgG1 memory B cell antigen receptor annexed immunoglobulin IgG1 heavy chain gene IGHG1 (referred to as hIgG1-G396R) protects against the occurrence and development of colorectal cancer, and analyzes the IgG1 memory B cells Mechanisms of action and potential applications in remodeling the tumor-anticancer microenvironment
.
Previous research by Prof.
Wanli Liu's group (Chen et al, Science, 2018) found that the hIgG1-G396R variant makes the intracellular tyrosine signal transduction motif of the IgG1 memory B cell antigen receptor and the Src family tyrosine The increased affinity of acid kinase Lyn reduces the immune activation threshold of IgG1 memory B cells, which in turn enhances clonal proliferation and plasma cell differentiation after such memory B cells recognize relevant antigens
.
Based on this, Professor Liu Wanli's research group and Professor Shen Zhanlong's research group worked together to conduct epidemiological analysis on a cohort of more than 1,000 colorectal cancer patients with ten-year follow-up information in the Department of Gastrointestinal Surgery of Peking University People's Hospital, and found that hIgG1-G396R homozygous Genotype tumor patients had significantly improved overall survival (OS, HR=0.
504, P=0.
007) and progression-free survival (PFS, HR=0.
57, P=0.
018).
Further multivariate COX risk analysis revealed that hIgG1- G396R homozygous genotype is an independent protective prognostic survival factor in colorectal cancer patients
.
In order to analyze the molecular mechanism of hIgG1-G396R in resisting the occurrence and development of colorectal cancer, the research group constructed mIgG2c-G400R gene knock-in mice (mIgG2c-G400R-KI mice), and applied tumor cell transplantation models and chemical mutagenesis of inflammatory progenitors.
A colorectal cancer model was further explored in mice, and it was found that colon adenocarcinoma cells MC38 and melanoma cells B16F10 were significantly affected by subcutaneous inoculation of mIgG2c-G400R-KI mice compared with wild-type control mice.
Inhibition; in a chemically mutagenized inflammatory primary colorectal cancer model, mIgG2c-G400R-KI mice also showed significantly reduced pathological phenotypes, including weight loss rate, disease activity index, tumor microenvironment inflammation level, etc.
Colon anatomical analysis at the end point of the primary tumor model further confirmed the presence of fewer and smaller colon tumors in the gut of mIgG2c-G400R-KI mice
.
Immune mechanism exploration found that in these two colon cancer animal models, mIgG2c-G400R-KI mice produced significantly higher levels of tumor-associated antibodies of the IgG2 subtype than WT mice, and had higher levels of IgG2c+ plasma in tumor tissues cell infiltration
.
In order to further study the molecular mechanism of memory B cell antigen receptor activation, the research group further constructed mIgG2c intracellular domain-deficient mice, and then in three different types of memory B cell antigen receptor membrane-linked antibody heavy chain intracellular In mice genetically modified in the signal transduction region, inoculated with tumor cells expressing OVA antigen, subsequent analysis found that there was a significant negative correlation between tumor size and OVA-specific IgG2c titer; more importantly, the spleen and bone marrow of mIgG2c-G400R-KI mice The proportions of germinal center B cells, plasma cells, and memory B cells of OVA-specific IgG2c subtype were significantly up-regulated compared with the other two types of genetically modified mice
.
Consistent with the above results, in the colon cancer model, IgG2c+ plasma cells were significantly increased in the mesenteric lymph nodes and intestinal lamina propria of mIgG2c-G400R-KI mice, and tumor drainage in mIgG2c-G400R-KI mice after MC38 inoculation IgG2c+ memory B cells were also significantly increased in lymph nodes, demonstrating that this variant increases memory B cell differentiation into plasma cells and promotes memory B cell infiltration in draining lymph nodes and the tumor microenvironment
.
Analysis of surgical samples from clinical patients further confirmed that tumor patients with hIgG1-G396R homozygous genotype also had more IgG1+ plasma cells and antibody infiltration in the tumor microenvironment
.
The humoral immunity dominated by B lymphocytes, the cellular immunity dominated by T lymphocytes, and the innate immunity dominated by innate immune cells have always influenced and closely related to each other in the tumor microenvironment
.
In order to further explore the immunological mechanism behind the above results, the research group used a variety of research methods such as flow cytometry and immunohistochemical staining, and found that the tumors of hIgG1-G396R homozygous genotype tumor patients and mIgG2c-G400R-KI mice In the microenvironment, the infiltration level and activation level of cDC1 DC cells and CD8+ T cells were significantly increased, and more importantly, the chemokine transcription level and the area, number and activity of tertiary lymphoid structures in the tumor microenvironment were also significantly increased
.
As a further independent confirmation of the core conclusions of the paper, the single-cell transcriptional analysis of colorectal cancer tumor tissue in collaboration with Professor Zhang Zemin and Dr.
Zhang Lei (now Shenzhen Bay Laboratory Distinguished Researcher) of Peking University found that patients with hIgG1-G396R homozygous genotype IgG+ plasma cells, CXCR5+ follicular helper T cells, CXCR6+ activated helper T cells, CD6+ tumor-resident CD8+ T cells, and CD160+ intraepithelial CD8+ T cells were all up-regulated in the tumor microenvironment of tumor cells, while Treg cells and LAYN+ depleted Sexual CD8+ T cells were characterized by downregulation
.
The aforementioned results demonstrate that hIgG1-G396R not only affects the differentiation of plasma cells and the production of tumor-specific antibodies in tumor tissue, but also enhances the overall anti-tumor immunity in the tumor tissue microenvironment by changing the immune microenvironment of tumor patients
.
In order to further explore how the enhanced antibody response affects the tumor microenvironment, the research group found that G400R mice had higher concentrations of antigen-specific antibodies to enhance the phagocytic ability of phagocytes, and the IgG-coated IgG purified in the serum of G400R mice Tumor cells can enhance the ability of DCs to present antigens to T cells
.
Finally, adoptive transfer of tumor-associated B cells or antibodies derived from mIgG2c-G400R mice showed therapeutic efficacy in a mouse tumor model, explaining the potential clinical implications
.
To sum up, this paper starts from the hIgG1-G396R variant enhancing the immune activation of memory B cells and the differentiation of plasma cells and even the production of IgG1 antibodies, and carries out a clinical correlation analysis of a large clinical cohort of colorectal cancer patients, to a genetically modified mouse model.
Combined with the study of colorectal cancer models, and the analysis of cell infiltration in the tumor microenvironment based on flow cytometry and immunohistochemistry, to the analysis of cell interactions based on laser confocal microscopy, and finally ending with single-cell sequencing studies of clinical samples
.
This series of multidisciplinary cross-type studies show that hIgG1-G396R is one of the protective prognostic factors in patients with colorectal cancer, revealing that hIgG1-G396R has the potential to be used as a prognostic indicator for patients in the field of colorectal cancer.
The guidelines provide reference value, and also suggest that adoptive transfer of IgG1+ B cells may be one of the powerful strategies for cancer immunotherapy, and inspire more researchers to explore the possibility of applying B cells to immunotherapy
.
The results of this series of studies have deepened people's understanding of the function and protective immunological mechanism of memory B cells in colorectal cancer, and made reasonable predictions for the prognostic level and clinicopathological characteristics of patients with clinically different genotypes of colorectal cancer.
It also provides an innovative research model for adoptive transfer of memory B cells to treat cancer
.
Schematic illustration of the IgG1 memory B-cell antigen receptor membrane-linked heavy chain hIgG1-G396R variant remodeling the colorectal cancer tumor microenvironment and enhancing antitumor immunity
.
The left is the control group, and the right is the enhanced anti-tumor immune microenvironment in patients with hIgG1-G396R homozygous genotype tumors: including enhanced TLS structure and function, increased IgG1+ plasma cell differentiation and infiltration, up-regulated IgG1 antibody infiltration, and then Functions through opsonization of antibody constant regions (ADCP, ADC, etc.
)
.
Dr.
Yang Bing has graduated from Liu Wanli's research group, Dr.
Zhang Zhen has graduated from Shen Zhanlong's research group, and Dr.
Chen Xiangjun has graduated from Liu Wanli's research group.
They are the co-first authors of this paper
.
Professor Liu Wanli of Tsinghua University and Professor Shen Zhanlong of Peking University People's Hospital are the co-corresponding authors of the paper
.
Original link: https:// Publisher: 11 Reprint Notice [Non-original article] The copyright of this article belongs to the author of the article, and personal sharing is welcome.
Reprinting is prohibited without permission.
The author owns All legal rights, violators will be prosecuted
.
