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
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...
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BMJ Publishing Group
2025-04-01
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| Series: | Journal for ImmunoTherapy of Cancer |
| Online Access: | https://jitc.bmj.com/content/13/4/e010879.full |
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| author | Joseph G Matous Jeremy P Snook Nico A Contreras Andrew G Ramstead Krystal R Charley Elizabeth M Kolawole Jacob N Kisiolek Kaitlyn A Flint Ashleigh J Soedel Breyana Robinson Anaiya B Mendoza Yohichi Kumaki Brian D Evavold Matthew A Williams |
| author_facet | Joseph G Matous Jeremy P Snook Nico A Contreras Andrew G Ramstead Krystal R Charley Elizabeth M Kolawole Jacob N Kisiolek Kaitlyn A Flint Ashleigh J Soedel Breyana Robinson Anaiya B Mendoza Yohichi Kumaki Brian D Evavold Matthew A Williams |
| author_sort | Joseph G Matous |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-af487e41aea547e0b4d80effeb9a512e |
| institution | OA Journals |
| issn | 2051-1426 |
| language | English |
| publishDate | 2025-04-01 |
| publisher | BMJ Publishing Group |
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| series | Journal for ImmunoTherapy of Cancer |
| spelling | doaj-art-af487e41aea547e0b4d80effeb9a512e2025-08-20T02:12:50ZengBMJ Publishing GroupJournal for ImmunoTherapy of Cancer2051-14262025-04-0113410.1136/jitc-2024-010879Shp-1 regulates the activity of low-affinity T cells specific to endogenous self-antigen during melanoma tumor growth and drives resistance to immune checkpoint inhibitionJoseph G Matous0Jeremy P Snook1Nico A Contreras2Andrew G Ramstead3Krystal R Charley4Elizabeth M Kolawole5Jacob N Kisiolek6Kaitlyn A Flint7Ashleigh J Soedel8Breyana Robinson9Anaiya B Mendoza10Yohichi Kumaki11Brian D Evavold12Matthew A Williams132 Huntsman Cancer Institute, Salt Lake City, Utah, USA1 Department of Pathology, The University of Utah, Salt Lake City, Utah, USA1 Department of Pathology, The University of Utah, Salt Lake City, Utah, USA1 Department of Pathology, The University of Utah, Salt Lake City, Utah, USA1 Department of Pathology, The University of Utah, Salt Lake City, Utah, USA1 Department of Pathology, The University of Utah, Salt Lake City, Utah, USA1 Department of Pathology, The University of Utah, Salt Lake City, Utah, USA1 Department of Pathology, The University of Utah, Salt Lake City, Utah, USA1 Department of Pathology, The University of Utah, Salt Lake City, Utah, USA3 North Carolina Agricultural and Technical State University, Greensboro, North Carolina, USA4 Spelman College, Atlanta, Georgia, USA1 Department of Pathology, The University of Utah, Salt Lake City, Utah, USA1 Department of Pathology, The University of Utah, Salt Lake City, Utah, USA1 Department of Pathology, The University of Utah, Salt Lake City, Utah, USABackground 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.https://jitc.bmj.com/content/13/4/e010879.full |
| spellingShingle | Joseph G Matous Jeremy P Snook Nico A Contreras Andrew G Ramstead Krystal R Charley Elizabeth M Kolawole Jacob N Kisiolek Kaitlyn A Flint Ashleigh J Soedel Breyana Robinson Anaiya B Mendoza Yohichi Kumaki 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 Journal for ImmunoTherapy of Cancer |
| title | 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 |
| title_full | 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 |
| title_fullStr | 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 |
| title_full_unstemmed | 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 |
| title_short | 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 |
| title_sort | 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 |
| url | https://jitc.bmj.com/content/13/4/e010879.full |
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