Activated B cells modulate the maturation of MDSCs via CD36-dependent MHC-II transfer to orchestrate CD4+ Th1-dominant antitumor immunity after cryo-thermal therapy.

Abstract

Immunotherapy, particularly immune checkpoint inhibitors (ICIs), has shown great success in treating various cancer types. However, the therapeutic efficacy of ICIs remains unsatisfactory because of the immunosuppressive tumor microenvironment. Cryo-thermal therapy (CTT), a novel tumor ablation approach developed by our laboratory, transforms the tumor immunosuppressive environment into an immunostimulatory environment by activating both innate and adaptive immunity. CTT promotes the differentiation of myeloid-derived suppressor cells (MDSCs) into mature dendritic cells and macrophages, activates antigen-presenting cells and natural killer (NK) cells, and induces Th1-dominant CD4⁺ T-cell-mediated antitumor immunity in numerous highly metastatic tumor models. However, the role of B cells in CTT-induced antitumor immunity remains unclear despite their critical function in adaptive immunity. Here, in vivo B-cell depletion with anti-CD20 monoclonal antibodies in multiple tumor models revealed that B cells play a crucial role in suppressing tumor metastasis and extending survival. More interestingly, CTT-activated B cells reprogram MDSCs to a mature phenotype through CD36-dependent major histocompatibility complex class II (MHC-II) transfer, resulting in enhanced Th1-dominant CD4⁺ T-cell responses and CD8⁺ T-cell cytotoxicity. These findings reveal a novel mechanism of B-cell-mediated modulation of the tumor microenvironment and provide insights into enhancing the efficacy of immunotherapy strategies.