An antibody targeting an immune checkpoint molecule BTN2A2 enhances anti-tumor immunity

Tumors exploit immune checkpoints to evade immune responses. Therefore, targeting these checkpoints has become a key strategy in cancer immunotherapy. In this study, we have developed a novel immune checkpoint inhibitor (ICI) targeting the B7 family-related molecule BTN2A2. The human BTN2A2 protein, which was highly expressed in some tumor tissues and activated antigen-presenting cells (APCs), can inhibit T cell activation and proliferation. The anti-BTN2A2 monoclonal antibody (mAb) can neutralize the inhibitory effect of BTN2A2 on T cells. In mouse models of pancreatic cancer and glioma, compared to the control group, the anti-BTN2A2 treatment group exhibited tumor shrinkage of 35.8 % (P < 0.05) and 51.2 % (P < 0.01), respectively, along with increased CD8+ tumor-infiltrating lymphocytes (TILs) by 1.7-fold (P < 0.001) and 2.2-fold (P < 0.001), respectively. In addition, anti-BTN2A2 mAb also increased the infiltration of B cells, M1 macrophages, and the expression of inflammatory cytokines in T cells, while reducing the infiltration of M2 macrophages, myeloid-derived suppressor cells (MDSCs), and regulatory T cells (Tregs). Thus, anti-hBTN2A2 mAb normalizes the immunodeficient tumor microenvironment (TME) and inhibits tumor growth. Our results suggest that targeting the BTN2A2 immune checkpoint may represent a novel strategy for cancer treatment, especially in immunosuppressive 'cold' tumors.