Abstract 606: Cis-B7:CD28 interactions at invaginated synaptic membranes activate CD28 and promote T cell function

Absence of adequate CD28 costimulation is a common feature of dysfunctional T cells in cancer. However, although augmentation of CD28 signaling is well known to be essential for restoring dysfunctional T cell immune responses upon immune checkpoint blockade treatment, it is unclear how CD28 in tumor-infiltrated T cells is activated in the absence of corresponding ligands on cancer. In current dogma, the T cell CD28 can be activated in trans by CD80 (B7-1) or CD86 (B7-2) expressed on professional antigen presenting cells (APCs) enriched in secondary lymphoid organs. Notably, besides professional APCs, B7 ligands are also displayed by T cells, but their functions are unclear. Here we report that B7 ligands expressed on T cells interact with CD28 in cis at membrane invaginations of the immunological synapse, as a result of phosphoinositide-3-kinase (PI3K) mediated membrane remodeling. Cis-B7:CD28 interactions triggered CD28 signaling through protein-kinase-C-theta (PKCθ) and promoted T cell survival, migration and cytokine production. In a B7 deficient tumor model grafted with primed CD8+ T cells, blockade of T cell intrinsic B7:CD28 interactions accelerated tumor growth and decreased intratumoral T cells. Thus, B7 ligands on T cells can evoke cell autonomous CD28 costimulation in cis in peripheral tissues, suggesting cis-signaling as a general mechanism for boosting T cell functionality. Citation Format: Yunlong Zhao, Christine Caron, Ya-Yuan Chan, Calvin K. Lee, Xiaozheng Xu, Jack D. Bui, Enfu Hui. Cis-B7:CD28 interactions at invaginated synaptic membranes activate CD28 and promote T cell function [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 606.