An Asia-specific variant of human IgG1 represses colorectal tumorigenesis by shaping the tumor microenvironment
Bing Yang, … , Zhanlong Shen, Wanli Liu
Bing Yang, … , Zhanlong Shen, Wanli Liu
Published February 8, 2022
Citation Information: J Clin Invest. 2022;132(6):e153454. https://doi.org/10.1172/JCI153454.
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Research Article Immunology Oncology

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.

Authors

Bing Yang, Zhen Zhang, Xiangjun Chen, Xu-Yan Wang, Shishang Qin, Liaoqi Du, Changjiang Yang, Liyu Zhu, Wenbo Sun, Yongjie Zhu, Qinwen Zheng, Shidong Zhao, Quan Wang, Long Zhao, Yilin Lin, Jinghe Huang, Fan Wu, Lu Lu, Fei Wang, Wenjie Zheng, Xiao-Hua Zhou, Xiaozhen Zhao, Ziye Wang, Sun Xiao-Lin, Yingjiang Ye, Shan Wang, Zhanguo Li, Hai Qi, Zemin Zhang, Dong-Ming Kuang, Lei Zhang, Zhanlong Shen, Wanli Liu

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Figure 1

The hIgG1-G396R variant protects against colorectal tumorigenesis and progression.

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The hIgG1-G396R variant protects against colorectal tumorigenesis and pr...
(A) Survival analyses of 1006 CRC patients with available follow-up information stratified by genotype. WT is indicated as the CC genotype, hIgG1-G396R heterozygous is denoted as CT, and hIgG1-G396R homozygous is denoted as TT. (B and C) Survival curves for 1006 CRC patients, classified by (B) recessive model and (C) dominant model. (D and E) Forest plots showing hazard ratios by (D) univariable COX regression and (E) multivariable COX regression analysis for correlation with the OS of CRC patients. (F–I) OS curves of 1006 CRC patients with different clinical treatments and clinical manifestations. Statistical significance was determined using a log-rank test (A–C and F–I). HR, hazard ratio; CI, confidence interval. Data are presented as the mean ± SEM.