Abstract SY19-02: A convergence of myeloid cells and T cells controls cancer immunity

Abstract

Abstract Although the advent of checkpoint inhibitors has completely transformed both oncology practice and the way we think about the immune system in cancer, their underlying mechanisms of action are only now starting to become clear. Recently, there has been increasing interest in the combination of antibodies blocking two co-inhibitory receptors on T cells, PD-1 and TIGIT, with randomized phase II results in non-small cell lung cancer having yielded significant overall survival benefit. We have investigated the mechanistic rationale for this combination and found that the inhibition of both co-inhibitory receptors is required to most effectively re-activate the two co-stimulatory receptors controlled by PD-1 (CD28) and TIGIT (CD226). Indeed, both co-stimulatory receptors serve as clients of PD-1 which recruits cytosolic phosphatases (eg SHP2) to inactivate the ITAM motifs in both CD28 and CD226. TIGIT acts to inhibit CD226 function in T cells solely by outcompeting it for ligand (CD155/PVR) binding. Unexpectedly, preclinical studies have demonstrated that ligand blocking antibodies to TIGIT are most effective when they contain a functional Fc domain. This observation suggests that at some level, Fc receptor-bearing cells play a role in mediating the function of anti-TIGIT blockade. Although this may reflect a modulation of T regulatory cell or NK cell function, both of which are TIGIT-positive, there are several observations that implicate the involvement of myeloid cells, namely macrophages and dendritic cells. One such observation is the fact that in the case of PD-1 blockade, the most relevant pool of PD-L1 turns out to be expressed by dendritic cells: in mice, genetic elimination of PD-L1 expression by tumor cells or macrophages exerts little effect on tumor growth, whilst PD-L1 elimination from dendritic cells greatly enhances endogenous anti-tumor immunity (Oh et al., 2020, Nature Cancer). This result further suggests, as is now becoming more widely accepted, that PD-L1/PD-1 blockade primarily acts by enhancing the activation of tumor-specific T cells during antigen presentation by dendritic cells, rather than by the rejuvenation of exhausted intratumoral T cells. Given the client relationship between PD-1 and CD28/CD226, it seems reasonable that TIGIT blockade similarly works at the level of antigen-presenting myeloid cells, either dendritic cells or macrophages. In the case of TIGIT, the requirement for an intact Fc domain further implies that T cell-bound anti-TIGIT may work as an opsonin that concomitantly triggers Fcγ receptor signaling to alter the functional status of the myeloid compartment. Thus, not only is there a convergence between the PD-1 and TIGIT pathways, but also a convergence between T cells and myeloid cells that may be essential for the function of these regulatory pathways and for the therapeutic effect associated with their blockade. Citation Format: Ira Mellman. A convergence of myeloid cells and T cells controls cancer immunity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr SY19-02.