Neoantigens promote effective response to combinatorial immunotherapies in triple-negative breast cancer through B cells 2347

Abstract Description Triple-negative breast cancer (TNBC) is a rare molecular subtype of breast cancer, with high aggressiveness, low survival rate and poor response to current immune checkpoint therapies (ICT). TNBC is a heterogeneous disease made of neoantigen-rich and neoantigen-negative cells, with the last one escaping immune recognition and seeding for recurrence. B cells are emerging as crucial components of the tumor microenvironment (TME) in TNBC, having strong predictive and prognostic significance to ICT. By using preclinical mouse models of TNBC we show that the presence of neoantigens induces anti-tumor B cell responses. Additionally, combinatorial ICT (αPD1+αCTLA4) promotes better responses to orthotopic, high tumor mutation burden TNBCs, as compared to monotherapies. However, how neoantigens and combinatorial ICT enhance B cell activity and therapy response is not known yet. By multi-omics and multi-parametric flow cytometry we observed that neoantigens remove immune suppressive features from the TME, by lowering T regulatory cell proportions and immune suppressive signals. Moreover, combinatorial ICT and neoantigens drive multi-clonal expansion of polyreactive B cells stemming from germinal centers and extrafollicular responses that generate plasma cells, activation of CD4+ and CD8+ T cells and NK cells tumor infiltration. Our research is decoding the processes that enhance immunotherapy of TNBC and elicit effective responses through anti-tumor B cell activity Funding Sources The research is supported by Susan G Komen Career Catalyst Award, funds from the California Breast Cancer Research Program, and funding from the Salk Institute and NIH P30 CA014195 to Daniel Hollern. Topic Categories Tumor Immunology: Cellular Responses and Tumor Microevironment (TIME)