黑色素瘤是最致命的皮肤癌，随着检查点阻断免疫疗法 (CBI) 的出现，治疗方法发生了变革。了解浸润肿瘤的免疫细胞的复杂网络、协调黑色素瘤细胞的控制以及对 CBI 的反应目前至关重要。有证据强调组织驻留记忆 (TRM) CD8 T 细胞和经典树突状细胞 1 型 (cDC1) 在癌症保护中的重要性。转录组学研究也支持 TCF7（编码 TCF1）T 细胞的存在对于免疫治疗反应最重要，尽管由于有证据表明 TCF1 下调导致组织驻留激活，因此是否存在 TCF1 TRM T 细胞存在不确定性。我们使用了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 TRM CD8 T 细胞和 cDC1：一组未接受免疫治疗，另一组接受免疫治疗。第一个队列被分为无疾病或诊断后 2 年有转移的患者，第二个队列被分为 CBI 应答者和无应答者。我们的研究确定了两个 CD8 TRM 子集：TCF1 和 TCF1-，与黑色素瘤保护相关。 TCF1 TRM 细胞显示出 IFN-γ 和 Ki67 表达增加，而 TCF1-TRM 细胞显示出细胞毒性分子表达增加。在转移性患者中，TRM 子集的标记物表达发生变化，TCF1 子集显示耗竭标记物的表达增加。我们观察到cDC1和TRM之间存在密切的空间相关性，TCF1 TRM/cDC1对在基质中富集，而TCF1-TRM/cDC1对在肿瘤区域中富集。值得注意的是，这些 TCF1-TRM 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 子集以及 cDC1 都被证明与 CBI 反应相关。我们的研究支持 TRM CD8 T 细胞和 cDC1 在黑色素瘤保护中的重要性，同时也强调了功能独特的 TCF1 和 TCF1-TRM 子集的存在，这两者对于黑色素瘤保护至关重要。黑色素瘤控制和 CBI 响应。© 作者（或其雇主）2024。根据 CC BY-NC 允许重复使用。禁止商业再利用。请参阅权利和权限。由英国医学杂志出版。

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.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.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.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.© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.