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

in Neoplasia (New York, N.Y.) by Li Xiao, Rong Hu, Wei Chen, Jie Gao, Youbo Zhao, Zuli Wang, Guangshi Du, Yishen Tian, Laijun Lai, Lu Liu, Min Su

TLDR

  • A new immunotherapy targets the B7 family-related molecule BTN2A2, showing promise in shrinking tumors and enhancing immune function in mouse models of pancreatic cancer and glioma.

Abstract

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.

Overview

  • The study develops a novel immune checkpoint inhibitor targeting the B7 family-related molecule BTN2A2.
  • The anti-BTN2A2 monoclonal antibody (mAb) can neutralize the inhibitory effect of BTN2A2 on T cells.
  • The study tests the anti-BTN2A2 mAb in mouse models of pancreatic cancer and glioma, evaluating its effects on tumor shrinkage, T cell infiltration, and immune cell subsets.

Comparative Analysis & Findings

  • 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) in pancreatic cancer and glioma mouse models, respectively.
  • The anti-BTN2A2 mAb increased CD8+ tumor-infiltrating lymphocytes (TILs) by 1.7-fold (P < 0.001) and 2.2-fold (P < 0.001) in pancreatic cancer and glioma mouse models, respectively.
  • The treatment 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).

Implications and Future Directions

  • Targeting the BTN2A2 immune checkpoint may represent a novel strategy for cancer treatment, especially in immunosuppressive 'cold' tumors.
  • Future studies can explore the anti-BTN2A2 mAb's effectiveness in combination with other immunotherapies or checkpoint inhibitors.
  • The study's findings suggest that identifying and characterizing novel immune checkpoints, such as BTN2A2, may uncover new opportunities for cancer immunotherapy.
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