Abstract 6391: Development of a novel strategy for cancer immunotherapy based on tumor immunogenicity improvement by HLA-drug interaction

Abstract [Purpose] Tumors with low T cell infiltrates (poor immunogenicity) display lower probability of clinical response to immune checkpoint inhibitors. To achieve higher immunotherapy efficacy, it is imperative to establish a novel strategy for improving immunogenicity. Abacavir (ABC), an anti-HIV drug, binds to the specific allele of human leukocyte antigen (HLA-B*57:01) and activate CD8+ T cells by presenting altered abnormal peptides. In this study, we considered the immune interaction between ABC and HLA-B*57:01 improving immunogenicity in poorly immunogenic tumors leading to a potent anti-cancer effect. [Methods] Mice were inoculated subcutaneously with tumor cells into the right flanks and interperitoneally treated with either ABC 5 mg or vehicle (water) for consecutive 9 days (B16F10) or 13 days (3LL) after tumor inoculation. Each tumor size was measured using vernier calipers on every 2 days. Activation, proliferation, and IFN-γ secretion of tumor infiltrating CD8+ T cells were analyzed by FACS. [Results and Discussion] ABC treatment showed significant tumor growth inhibition associated with CD8+ T cell infiltration into tumor in mice inoculated with HLA-B*57:01 expressing B16F10 melanoma or Lewis lung carcinoma (3LL) cells, but neither in HLA-B*57:03 (negative allele)-expressing nor control tumors inoculated mice. Moreover, the tumor infiltrating CD8+ T cell were immune-activated and proliferated, with secreting IFN-γ. In contrast, ABC-induced anti-tumor effect was abrogated in CD8+ T cell-depleted mice, IFN-γ KO mice, and CXCR3-blocked mice. The combination therapy with anti-PD-1 antibody treatment induced better inhibition of tumor growth than ABC monotherapy in HLA-B*57:01 expressing B16F10 inoculated mice. These results suggested that ABC/HLA-B*57:01 interaction could improve tumor immunogenicity associated with CD8+ T cell-mediated anti-tumor effect in poorly immunogenic tumors. This finding lays a foundation to develop a novel drug-induced cancer immunotherapy targeting immune resistant tumors. Citation Format: Takeshi Susukida, So-ichiro Sasaki, Tomohiro Shirayanagi, Shigeki Aoki, Kousei Ito, Yoshihiro Hayakawa. Development of a novel strategy for cancer immunotherapy based on tumor immunogenicity improvement by HLA-drug interaction [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6391.