选择两例具有患者来源的细胞系、外周血和肿瘤浸润性 T 细胞的超突变结肠癌病例来详细研究免疫反应。与自体肿瘤细胞共培养的 T 细胞仅显示低水平的促炎细胞因子，并且在肿瘤识别。同样，用免疫检查点抑制剂（ICI）进行共培养物的治疗并不能增强抗肿瘤免疫反应。由于在肿瘤细胞中检测到蛋白酶抑制剂 9 (PI-9)，因此在 T 细胞细胞毒性测试中除了 ICI 之外还使用了特异性抑制剂 (PI-9i)。然而，只有用肿瘤特异性肽（隐性和新抗原）进行预刺激才能显着增加 T 细胞对肿瘤细胞的识别和消除，而与 ICI 或 PI-9i 无关。我们表明，肿瘤引发的药物可以靶向 ICI 抗性肿瘤细胞T 细胞，还证明了未经肿瘤处理的外周血 T 细胞与高度耗尽的肿瘤浸润 T 细胞相比的优越性。未来的精准免疫治疗方法应包括多模式策略，以成功诱导持久的抗肿瘤免疫反应。© 2024。作者。

Two hypermutated colon cancer cases with patient-derived cell lines, peripheral and tumor-infiltrating T cells available were selected for detailed investigation of immunological response.T cells co-cultured with autologous tumor cells showed only low levels of pro-inflammatory cytokines and failed at tumor recognition. Similarly, treatment of co-cultures with immune checkpoint inhibitors (ICI) did not boost antitumor immune responses. Since proteinase inhibitor 9 (PI-9) was detected in tumor cells, a specific inhibitor (PI-9i) was used in addition to ICI in T cell cytotoxicity testing. However, only pre-stimulation with tumor-specific peptides (cryptic and neoantigenic) significantly increased recognition and elimination of tumor cells by T cells independently of ICI or PI-9i.We showed, that ICI resistant tumor cells can be targeted by tumor-primed T cells and also demonstrated the superiority of tumor-naïve peripheral blood T cells compared to highly exhausted tumor-infiltrating T cells. Future precision immunotherapeutic approaches should include multimodal strategies to successfully induce durable anti-tumor immune responses.© 2024. The Author(s).