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An Asia-specific variant of human IgG1 represses colorectal tumorigenesis by shaping the tumor microenvironment.

ABSTRACT: Emerging studies have focused on ways to treat cancers by modulating T cell activation. However, whether B cell receptor signaling in the tumor microenvironment (TME) can be harnessed for immunotherapy is unclear. Here, we report that an Asia-specific variant of human IgG1 containing a Gly396 to Arg396 substitution (hIgG1-G396R) conferred improved survival of patients with colorectal cancer (CRC). Mice with knockin of the murine functional homolog mIgG2c-G400R recapitulated the alleviated tumorigenesis and progression in murine colon carcinoma models. Immune profiling of the TME revealed broad mobilizations of IgG1+ plasma cells, CD8+ T cells, CD103+ DCs, and active tertiary lymphoid structure formation, suggesting an effective antitumor microenvironment in hIgG1-G396R CRC patients. Mechanistically, this variant potentiated tumor-associated antigen-specific (TAA-specific) plasma cell differentiation and thus antibody production. These elevated TAA-specific IgG2c antibodies in turn efficiently boosted the antibody-dependent tumor cell phagocytosis and TAA presentation to effector CD8+ T cells. Notably, adoptive transfer of TAA-specific class-switched memory B cells harboring this variant exhibited therapeutic efficacy in murine tumor models, indicating their clinical potential. All these results prompted a prospective investigation of hIgG1-G396R in patients with CRC as a biomarker for clinical prognosis and demonstrated that manipulating the functionality of IgG1+ memory B cells in tumors could improve immunotherapy outcomes.

SUBMITTER: Yang B

PROVIDER: S-EPMC8920342 | biostudies-literature | 2022 Mar

REPOSITORIES: biostudies-literature

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An Asia-specific variant of human IgG1 represses colorectal tumorigenesis by shaping the tumor microenvironment.

Yang Bing B Zhang Zhen Z Chen Xiangjun X Wang Xu-Yan XY Qin Shishang S Du Liaoqi L Yang Changjiang C Zhu Liyu L Sun Wenbo W Zhu Yongjie Y Zheng Qinwen Q Zhao Shidong S Wang Quan Q Zhao Long L Lin Yilin Y Huang Jinghe J Wu Fan F Lu Lu L Wang Fei F Zheng Wenjie W Zhou Xiao-Hua XH Zhao Xiaozhen X Wang Ziye Z Xiao-Lin Sun S Ye Yingjiang Y Wang Shan S Li Zhanguo Z Qi Hai H Zhang Zemin Z Kuang Dong-Ming DM Zhang Lei L Shen Zhanlong Z Liu Wanli W

The Journal of clinical investigation 20220301 6

Emerging studies have focused on ways to treat cancers by modulating T cell activation. However, whether B cell receptor signaling in the tumor microenvironment (TME) can be harnessed for immunotherapy is unclear. Here, we report that an Asia-specific variant of human IgG1 containing a Gly396 to Arg396 substitution (hIgG1-G396R) conferred improved survival of patients with colorectal cancer (CRC). Mice with knockin of the murine functional homolog mIgG2c-G400R recapitulated the alleviated tumori ...[more]

PMID: 35133976

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Dataset Information

An Asia-specific variant of human IgG1 represses colorectal tumorigenesis by shaping the tumor microenvironment.

Publications

An Asia-specific variant of human IgG1 represses colorectal tumorigenesis by shaping the tumor microenvironment.

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