Adoptive cell therapy (ACT) using ex vivo–expanded tumor-infiltrating lymphocytes (TILs) can eliminate or shrink metastatic melanoma, but its long-term efficacy remains limited to a fraction of patients. Using longitudinal samples from 13 patients with metastatic melanoma treated with TIL-ACT in a phase 1 clinical study, we interrogated cellular states within the tumor microenvironment (TME) and their interactions. We performed bulk and single-cell RNA sequencing, whole-exome sequencing, and spatial proteomic analyses in pre- and post-ACT tumor tissues, finding that ACT responders exhibited higher basal tumor cell–intrinsic immunogenicity and mutational burden. Compared with nonresponders, CD8 + TILs exhibited increased cytotoxicity, exhaustion, and costimulation, whereas myeloid cells had increased type I interferon signaling in responders. Cell-cell interaction prediction analyses corroborated by spatial neighborhood analyses revealed that responders had rich baseline intratumoral and stromal tumor–reactive T cell networks with activated myeloid populations. Successful TIL-ACT therapy further reprogrammed the myeloid compartment and increased TIL-myeloid networks. Our systematic target discovery study identifies potential T-myeloid cell network–based biomarkers that could improve patient selection and guide the design of ACT clinical trials.

中文翻译：

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对肿瘤浸润淋巴细胞过继治疗的反应与黑色素瘤中预先存在的 CD8 + T 骨髓细胞网络有关

使用离体扩增的肿瘤浸润淋巴细胞（TIL）的过继细胞疗法（ACT）可以消除或缩小转移性黑色素瘤，但其长期疗效仍然仅限于一小部分患者。在一项 1 期临床研究中，我们使用来自 13 名接受 TIL-ACT 治疗的转移性黑色素瘤患者的纵向样本，研究了肿瘤微环境 (TME) 内的细胞状态及其相互作用。我们对 ACT 治疗前和治疗后的肿瘤组织进行了批量和单细胞 RNA 测序、全外显子组测序和空间蛋白质组学分析，发现 ACT 反应者表现出更高的基础肿瘤细胞内在免疫原性和突变负担。与无应答者相比，CD8+TIL 表现出细胞毒性、耗竭和共刺激增加，而骨髓细胞在应答者中 I 型干扰素信号传导增加。空间邻域分析证实的细胞间相互作用预测分析表明，应答者具有丰富的基线瘤内和间质肿瘤反应性 T 细胞网络，并具有激活的骨髓细胞群。成功的 TIL-ACT 疗法进一步重新编程了髓样区室并增加了 TIL-髓样网络。我们的系统性目标发现研究确定了基于 T 骨髓细胞网络的潜在生物标志物，可以改善患者选择并指导 ACT 临床试验的设计。