背景:黑色素瘤,最致命的皮肤癌,随着检查点阻断免疫疗法(CBI)的出现,经历了变革性的治疗转变。了解浸润肿瘤的免疫细胞的复杂网络并协调黑色素瘤细胞的控制和对CBI的反应目前至关重要。有证据强调了组织驻留记忆(TRM)CD8T细胞和经典的1型树突状细胞(cDC1)在癌症保护中的重要性。转录组学研究还支持TCF7+(编码TCF1)T细胞的存在,作为最重要的免疫治疗反应,尽管关于是否存在TCF1+TRMT细胞存在不确定性,因为有证据表明TCF1下调组织滞留激活。
方法:我们使用多重免疫荧光和光谱流式细胞术评估两个黑色素瘤患者队列中的TRMCD8T细胞和cDC1:一个未接受免疫治疗,另一个接受免疫治疗。第一个队列在诊断后2年无疾病或有转移的患者之间进行划分,而第二个队列在CBI应答者和无应答者之间进行划分。
结果:我们的研究确定了两个CD8+TRM亚群,TCF1+和TCF1-,与黑色素瘤保护相关。TCF1+TRM细胞显示IFN-γ和Ki67的高表达,而TCF1-TRM细胞显示细胞毒性分子的高表达。在转移性患者中,TRM子集经历了标记表达的转变,TCF1-亚群显示耗尽标志物的表达增加。我们观察到cDC1和TRM之间存在密切的空间相关性,TCF1+TRM/cDC1对富集在基质中,TCF1-TRM/cDC1对富集在肿瘤区域中。值得注意的是,这些TCF1-TRMs表达细胞毒性分子并与凋亡的黑色素瘤细胞相关。TCF1+和TCF1-TRM子集,与cDC1一起,证明与CBI反应相关。
结论:我们的研究支持TRMCD8T细胞和cDC1在黑色素瘤保护中的重要性,同时也强调了功能上独特的TCF1和TCF1-TRM亚群的存在,对黑素瘤控制和CBI反应都至关重要。
BACKGROUND: Melanoma, the most lethal form of skin cancer, has undergone a transformative treatment shift with the advent of checkpoint blockade immunotherapy (CBI). Understanding the intricate network of immune cells infiltrating the tumor and orchestrating the control of melanoma cells and the response to CBI is currently of utmost importance. There is evidence underscoring the significance of tissue-resident memory (TRM) CD8 T cells and classic dendritic cell type 1 (cDC1) in cancer protection. Transcriptomic studies also support the existence of a TCF7+ (encoding TCF1) T cell as the most important for immunotherapy response, although uncertainty exists about whether there is a TCF1+TRM T cell due to evidence indicating TCF1 downregulation for tissue residency activation.
METHODS: We used multiplexed immunofluorescence and spectral flow cytometry to evaluate TRM CD8 T cells and cDC1 in two melanoma patient cohorts: one immunotherapy-naive and the other receiving immunotherapy. The first cohort was divided between patients free of disease or with metastasis 2 years postdiagnosis while the second between CBI responders and non-responders.
RESULTS: Our study identifies two CD8+TRM subsets, TCF1+ and TCF1-, correlating with melanoma protection. TCF1+TRM cells show heightened expression of IFN-γ and Ki67 while TCF1- TRM cells exhibit increased expression of cytotoxic molecules. In metastatic patients, TRM subsets undergo a shift in marker expression, with the TCF1- subset displaying increased expression of exhaustion markers. We observed a close spatial correlation between cDC1s and TRMs, with TCF1+TRM/cDC1 pairs enriched in the stroma and TCF1- TRM/cDC1 pairs in tumor areas. Notably, these TCF1- TRMs express cytotoxic molecules and are associated with apoptotic melanoma cells. Both TCF1+ and TCF1- TRM subsets, alongside cDC1, prove relevant to CBI response.
CONCLUSIONS: Our study supports the importance of TRM CD8 T cells and cDC1 in melanoma protection while also highlighting the existence of functionally distinctive TCF1+ and TCF1- TRM subsets, both crucial for melanoma control and CBI response.