A germline variant of human IgG1+ B cell receptor represses colorectal tumorigenesis and progression by shaping the tumor microenvironment

Abstract

The presence of B lymphocytes in tumor tertiary lymphoid structures (TLSs) is an important prognostic indicator for different types of cancers. However, whether B cell responses in the tumor microenvironment (TME) can be harnessed for immunotherapy is unclear. Here we report that a protective germline variant of human immunoglobulin heavy constant gamma 1 gene (IGHG1) containing a Gly396 to Arg396 substitution (hIgG1-G396R) confers improved survival of colorectal cancer (CRC) patients. These hIgG1-G396R homozygous CRC patients displayed elevated tumor-associated antigen (TAA)-specific IgG1 antibody production and plasma cell infiltration into tumors. In murine colon carcinoma models, mice expressing the murine functional homolog IgG2c-Gly400Arg variant (mIgG2c-G400R) also produce higher levels of tumor-specific IgG2c antibodies via enhanced plasma cell differentiation, together with alleviated tumorigenesis and progression. Mechanistically, this variant potentiates TAA-specific antibody-dependent cellular phagocytosis and antigen presentation. Comprehensive immune profiling of the TME of CRC patients revealed that hIgG1-G396R prominently promotes broad mobilization of immune cells (IgG1+ plasma cells, CD8+ T cells, CD103+ DCs) and efficient TLS formation, both key components of an anti-tumor microenvironment. Notably, adoptive transfer of tumor-primed B cells with this variant exhibited therapeutic efficacy in murine tumor models, demonstrating clinical potential. These results prompt a prospective investigation of hIgG1-G396R in CRC patients as a biomarker for clinical prognosis and demonstrate that manipulating the functionality of IgG1+ B cells in tumors could improve immunotherapy outcomes.