Matous Joseph G, Snook Jeremy P, Contreras Nico A, Ramstead Andrew G, Charley Krystal R, Kolawole Elizabeth M, Kisiolek Jacob N, Flint Kaitlyn A, Soedel Ashleigh J, Robinson Breyana, Mendoza Anaiya B, Kumaki Yohichi, Evavold Brian D, Williams Matthew A
Department of Pathology, The University of Utah, Salt Lake City, Utah, USA.
Huntsman Cancer Institute, Salt Lake City, Utah, USA.
J Immunother Cancer. 2025 Apr 17;13(4):e010879. doi: 10.1136/jitc-2024-010879.
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.
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)-specific T cells and a micropipette-based two-dimensional affinity assay to measure the T cell receptor (TCR) affinity.
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-2. 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 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.
肿瘤微环境中活化的CD8 T细胞的存在与对免疫检查点抑制剂（ICI）治疗的有效免疫反应相关。然而，ICI主要靶向高亲和力T细胞，在新抗原较少的肿瘤中，这类细胞可能数量较少。联合ICI靶向细胞内磷酸酶含Src同源区2结构域的磷酸酶-1（Shp-1）可降低T细胞活化阈值，并增强低亲和力T细胞产生有效抗肿瘤反应的能力。
在本研究中，我们试图确定在肿瘤活跃生长期间对Shp-1进行短暂抑制是否能挽救对内源性自身抗原具有特异性的低亲和力T细胞的活性。为解决这个问题，我们将耶鲁大学小鼠黑色素瘤（YUMM）肿瘤细胞系植入野生型小鼠体内，待肿瘤形成后，给予Shp-1抑制剂（TPI-1），同时或不同时进行ICI治疗。我们通过流式细胞术分析肿瘤中免疫浸润的治疗依赖性变化、主要组织相容性复合体（MHC）四聚体介导的酪氨酸酶相关蛋白2（TRP-2）特异性T细胞检测以及基于微量移液器的二维亲和力测定来测量T细胞受体（TCR）亲和力。
对已建立YUMM肿瘤的小鼠给予ICI和Shp-1抑制剂，但单独使用任何一种药物均不能显著延迟肿瘤生长，且CD8肿瘤浸润性T细胞频率增加，效应功能增强且耗竭特征降低。特别是，联合治疗增加了对MHC I类限制性肿瘤自身抗原TRP-2具有特异性的CD8 T细胞频率。我们发现效应T细胞的增加几乎完全归因于TCR亲和力极低的T细胞的增加。
我们得出结论，改变TCR信号阈值的方法可有效增强在ICI耐药和/或无新抗原驱动抗肿瘤反应的情况下，对内源性自身抗原具有特异性的低亲和力T细胞的抗肿瘤反应。
