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T cell immunotherapy to solid tumor requires not only sufficient numbers of cancer cell-specific cytotoxic T cells, but also their infiltration into tumor tissues and the ability to resist hostile TME immunosuppression. Through a proprietary process, we have identified a unique reagent, termed KX147, of which treatment of tumor potently repolarizes the TME, resulting in abrogation of multi-axes immunosuppressive signal transduction pathways reprograme of the TME for innate and adaptive immunity against cancer. We found that immunotherapy-refractory solid tumors under therapies generally fail to induce intratumoral macrophages for proinflammatory phenotypic change, nor did they reprogram the TME towards anti-tumor immunogenicity. Rather, these tumors arbitrate strong resistance through increasing IL-10 production, TGFβ signaling (TGFBR1 and TGFBR2), and CCL2 chemokine that attracts MDSC, leading to wound healing and reinforcement of tumor immunosuppression. In stark contrast, tumors treated with KX147 exhibit completely different TME responses to checkpoint blockade, RT and other immune-modulatory therapies, and reshape intratumoral macrophages from immunosuppression to potent proinflammation, featuring high expressions of TNFα, IFNγ, IL-1β, IL-6, IL-12, IL-17, IL-18, etc., while abating IL-10 and TGFβ. Moreover, KX147 also induces a prominent immunogenic antigen presentation machinery with elevated cell surface MHC-I, MHC-II, and costimulatory molecules CD80, CD86, CD40, OX40L on macrophages, which through antigen presentation induces large expansion of tumor-specific T cells for tumor elimination. Together, our studies demonstrate a novel immunotherapy strategy with KX147 combination, which holds promises for rapid and systemic elimination of solid tumors and metastases to achieve cure. Citation Format: Lei Shi, Zhen Bian, Jane Zen, Harry Stylli, Yuan Liu. Overcome solid tumor immunosuppression for T cells-mediated cancer elimination [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 2337. |
