Modulating Tumor Infiltrating Myeloid Cells to Enhance BsAb-driven T Cell Infiltration and Anti-tumor Immune Responses

초록

The tumor microenvironment (TME) is a dynamic cellular milieu to promote tumor angiogenesis, growth, proliferation, and metastasis, while derailing the host anti-tumor response. The TME impedes bispecific antibody (BsAb) or chimeric antigen receptor (CAR)-driven T cells infiltration, survival, and cytotoxic efficacy. Modulating tumor infiltrating myeloid cells (TIMs) could potentially improve the efficacy of BsAb.We evaluated the effects of TIM modulation on BsAb-driven T cell infiltration into tumors, their persistence, and in vivo anti-tumor response. Anti-GD2 BsAb and anti-HER2 BsAb built on IgG-[L]-scFv platform were tested against human cancer xenografts in BALB-Rag2-/-IL-2R-γc-KO (BRG) mice. Tumor infiltrating lymphocytes (TILs) carrying luciferase reporter were quantified by bioluminescence. Antibodies specific for polymorphonuclear myeloid-derived suppressor cell (PMN-MDSC), monocytic MDSC (M-MDSC), and tumor associated macrophage (TAM) were used to study the role of each TIM component. Dexamethasone, an established anti-inflammatory agent, is tested for its effect on inhibitory TIMs. BsAb-driven T cells elicited a recruitment of myeloid cells into human tumor xenografts. Each TIM depleting therapy successfully depleted cells of interest in blood and in tumors. Depletion of PMN-MDSCs, M-MDSCs, or TAMs was associated with enhanced T cell infiltration into tumors, significantly improving tumor control and mice survival in multiple cancer xenograft models. Dexamethasone premedication, in a dose-dependent manner, depleted monocytes in circulation and TAMs in tumors, enhanced BsAb-driven T cell infiltration, and improved tumor control with survival benefit. Reducing TIM greatly enhanced anti-tumor effects of BsAb-directed T cell immunotherapy by improving intratumoral T cell infiltration and persistence. TAM depletion therapies including dexamethasone were more effective in infiltrating T cells into tumors and sustaining anti-tumor response of BsAb treatment.