Abstract LB126: Shp-1 regulates the activity of low affinity T cells specific to endogenous self-antigen during melanoma tumor growth and drives resistance to immune checkpoint inhibition

Abstract The presence of activated CD8 T cells in the tumor microenvironment (TME) is correlated with an effective immune response to immune checkpoint inhibitor (ICI) therapy. However, ICI predominately targets high affinity T cells, which are exhaustion-prone and may be less abundant in tumors with few neoantigens. Low affinity T cells are abundant during many anti-tumor responses, and there is a need to better understand their contribution to the ICI-induced response and to determine the mechanisms controlling their activation. 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. In this study, we sought to determine whether temporal inhibition of Shp-1 during active tumor growth could rescue the activity of low affinity T cells specific for endogenous self-antigens. To address this question, we implanted Yale University Mouse Melanoma (YUMM) tumor cell lines into WT mice, as the resulting tumors are ICI-resistant and lack abundant neo-antigens. Administration of ICI and a Shp-1 inhibitor to mice with established YUMM tumors, but neither agent alone, resulted in a significant delay in tumor growth and an increased frequency of CD8 tumor-infiltrating T cells with enhanced effector (PD-1+ Gzb+ Tbet+) and reduced exhaustion characteristics (2b4+ PD-1+). In particular, combined treatment increased the frequency of CD8 T cells specific for the MHC Class I-restricted tumor self-antigen TRP-2180-188. We utilized a micropipette-based 2D affinity assay to measure the T cell receptor (TCR) affinity of TRP-2-specific T cells in the tumor following treatment. We found that the increase in effector T cells was almost entirely due to an increase in T cells with very low TCR affinity. We conclude that approaches for altering TCR signaling threshold are effective in enhancing the anti-tumor response of low affinity T cells specific for endogenous self-antigens in settings of ICI resistance and/or where neo-antigens are not available to drive anti-tumor responses. Citation Format: Joseph G. Matous, Andrew G. Ramstead, Krystal R. Charley, Elizabeth M. Kolawale, Jacob N. Kisiolek, Brian D. Evavold, Matthew A. Williams. Shp-1 regulates the activity of low affinity T cells specific to endogenous self-antigen during melanoma tumor growth and drives resistance to immune checkpoint inhibition [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr LB126.