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

  • J Immunother Cancer. 2025 Apr 17;13(4):e010879. doi: 10.1136/jitc-2024-010879.
Joseph G Matous  1  2 ,  Jeremy P Snook  1  2 ,  Nico A Contreras  1  2 ,  Andrew G Ramstead  1  2 ,  Krystal R Charley  1  2 ,  Elizabeth M Kolawole  1 ,  Jacob N Kisiolek  1 ,  Kaitlyn A Flint  1  2 ,  Ashleigh J Soedel  1  2 ,  Breyana Robinson  3 ,  Anaiya B Mendoza  4 ,  Yohichi Kumaki  1  2 ,  Brian D Evavold  1 ,  Matthew A Williams  5  2
Affiliations
  • 1. Department of Pathology, The University of Utah, Salt Lake City, Utah, USA.
  • 2. Huntsman Cancer Institute, Salt Lake City, Utah, USA.
  • 3. North Carolina Agricultural and Technical State University, Greensboro, North Carolina, USA.
  • 4. Spelman College, Atlanta, Georgia, USA.
  • 5. Department of Pathology, The University of Utah, Salt Lake City, Utah, USA [email protected].
PMID: 40246583 DOI: 10.1136/jitc-2024-010879
Abstract

Background: The presence of activated CD8 T cells in the tumor microenvironment is correlated with an effective immune response to immune checkpoint inhibitor (ICI) therapy. However, ICI predominantly targets high-affinity T cells, which may be less abundant in tumors with few neoantigens. Targeting the intracellular Phosphatase Src homology region 2 domain-containing phosphatase-1 (Shp-1) in combination with ICI lowers the T cell activation threshold and enhances the ability of low-affinity T cells to mount a productive antitumor response.

Methods: 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 and, on tumor establishment, administered an inhibitor of Shp-1 (TPI-1) with or without ICI treatment. We analyzed treatment-dependent changes in the immune infiltrate in the tumor via flow cytometry, major histocompatibility complex (MHC) tetramer-mediated detection of tyrosinase-related protein 2 (TRP-2)180-188-specific T cells and a micropipette-based two-dimensional affinity assay to measure the T cell receptor (TCR) affinity.

Results: 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 and reduced exhaustion characteristics. 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 found that the increase in effector T cells was almost entirely due to an increase in T cells with very low TCR affinity.

Conclusions: We conclude that approaches for altering TCR signaling threshold are effective in enhancing the antitumor response of low-affinity T cells specific for endogenous self-antigens in settings of ICI resistance and/or where neoantigens are not available to drive antitumor responses.

Keywords
Immune Checkpoint Inhibitor; Immunotherapy; Melanoma; T cell; T cell Receptor - TCR.
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