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 4

Elevated numbers of infiltrating CD8+ T cells and DCs in the TME of the hIgG1-G396R variant.

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Elevated numbers of infiltrating CD8+ T cells and DCs in the TME of the ...
(A and B) Representative micrographs and cell density (in mm2) of (A) CD8+ T cells and (B) S100+ DCs in tumor sections from hIgG1-G396R homozygous and WT CRC patients by IHC. Scale bars: 200 μm. (C) Representative micrographs and cell density (in mm2) of CD8+ T cells in colon specimens from CAC-induced WT and mIgG2c-G400R mice, measured by IHC. Scale bars: 100 μm. (D) Quantification by flow cytometry, pregated on live CD45+ cells, of tumor-infiltrating CD8+ T cells in the tumor tissues on day 10 after MC38-mOVA tumor cell inoculation. (E) Quantification of tumor-infiltrating naive, central memory, and effector memory CD8+ T cells in the MC38-mOVA tumor tissues by flow cytometry, pregated on CD45+, CD3+, and CD8+ T cells. (F and G) Quantification of (F) IFN-γ–secreting and (G) granzyme B–secreting (GZMB-secreting) CD8+ T cells, pregated on CD45+, CD3+, and CD8+ T cells. (H–I) Quantification of tumor-infiltrating DC subtypes. One of 3 representative experiments is shown (D–I). Statistical significance was determined using an unpaired, 2-tailed Student’s t test (A–C) or 1-way ANOVA (D–I). Data are presented as the mean ± SEM.