Neoantigen-specific CD4+ T cells sustain endogenous intratumoral B cell responses to enhance anti-tumor immunity 2258511

Abstract

Abstract Introduction Cancer mutations can give rise to novel tumor-specific peptides (“neoantigens”) that are recognized by T cells to attack tumors. CD4+ T cells cooperate with B cells of related antigen specificity to promote antibody production and enhance antitumor immunity. Paradoxically, tumors are frequently coated with matured antibodies that recognize unmutated epitopes despite the existence of tolerance mechanisms. We hypothesized that neoantigen-specific CD4+ T cells play a key role in coordinating polyfunctional tumor-associated B cell responses. Methods To test this, we utilized an autochthonous KP (KrasG12D/+; tp53-/-) mouse model of lung cancer initiated via delivery of Cre, and leveraged flow cytometric and histological analyses with temporal perturbations, depletions, and ELISA assay. Results Tumors expressing a single MHC-II-restricted neoantigen (mITGB1) or lacking this neoantigen (mITGB1-neg) harbored similar densities of B cells. However, B cells in mITGB1+ tumors uniquely displayed hallmarks of germinal center entry, class switching, and differentiation, and many B cells were spatially confined to clusters containing T cells. B cells persisted in mITGB1+ tumors for at least three weeks when lymphocyte entry was blocked, while B cells in mITGB1-neg tumors disappeared in this setting. Serum IgG isolated from mITGB1+ but not mITGB1-neg tumor-bearing mice showed reactivity against a non-autologous, neoantigen-deficient KP-derived cell line despite the presence of germinal center B cells in the draining lymph nodes of mITGB1-neg tumors. Finally, B cell ablation led to increased tumor burden, loss of intratumoral T cell clusters, and altered T cell composition and positioning in the tumor bed. Conclusion Our data indicate that neoantigen-specific CD4+ T cells orchestrate local B cell responses within tumors to promote anti-tumor immunity. Intratumoral lymphocyte hubs may represent unique sites of B cell selection, and function as a source of cancer-targeting antibodies and antigenic spread. Funding Source Jane Coffin Childs Fund, Hope Funds for Cancer Research Topic Categories Tumor Immunology: Cellular Responses and Tumor Microevironment (TIME)