Abstract A071: Inhibition of Shp-1 in combination with checkpoint inhibitors broadens the repertoire of tumor-infiltrating self-antigen-specific T cells and drives therapeutic rescue of T cell function

Abstract While stimulation of CD8 T cells by immune checkpoint inhibitors (ICI) is effective in tumors with neoantigens and a high mutational burden, responsiveness is decreased in tumors with a low mutational burden and predominantly low-affinity tumor-self antigens. Targeting the intracellular phosphatase Src homology region 2 domain-containing phosphatase-1, Shp-1 (PTPN6), in combination with ICI lowers the T cell activation threshold and enhances the ability of low-affinity T cells to mount a productive anti-tumor response. However, the mechanisms behind this combinatorial effect are unclear. In this study, we aimed to determine whether temporal inhibition of Shp-1 (Shp-1i) during active tumor growth transcriptionally reprograms CD8 T cells and expands the tumor-self-antigen-specific repertoire. To address this question, we implanted Yale University Mouse Melanoma (YUMM1.1) tumor cells into WT mice, as the resulting tumors are ICI-resistant and lack abundant neo-antigens. MHC Class I-restricted tumor self-antigen TRP-2180-188 tetramer was used to isolate and measure the tumor self-antigen response. RNA single-cell sequencing and paired V(D)J sequencing were performed TRP-2-specific T cells isolated from the tumors of untreated and ICI+Shp-1i-treated mice. Following treatment TRP2-specific CD8 TIL largely converted from an exhausted (Lag3, Havcr2) to an effector (Gzmb, T-bet) transcriptional program while preserving a stem-like (Tcf7, Slamf6) population of expanded exhausted progenitor cells. V(D)J sequencing revealed that ICI+Shp-1i significantly expanded TRP2-specific CD8 clonal diversity in the tumor microenvironment, indicating the enhanced recruitment of sub-dominant or new TRP-2-specific T cell clones. We conclude that Shp-1i combines with ICI to broaden the repertoire of self-antigen-specific T cells and drive therapeutic rescue of T cell function through the recruitment of new clones that express a robust effector transcriptional program. Citation Format: Joseph G. Matous, Kaitlyn A. Flint, Christopher P. Hanson, Matthew A. Williams. Inhibition of Shp-1 in combination with checkpoint inhibitors broadens the repertoire of tumor-infiltrating self-antigen-specific T cells and drives therapeutic rescue of T cell function abstract. In: Proceedings of the AACR Immuno-Oncology Conference (AACR IO): Discovery and Innovation in Cancer Immunology: Revolutionizing Treatment through Immunotherapy; 2026 Feb 18-21; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Immunol Res 2026;14(2 Suppl):Abstract nr A071.