Response to tumor-infiltrating lymphocyte adoptive therapy is associated with preexisting CD8⁺ T-myeloid cell networks in melanoma.

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. Editor's summary: Adoptive cellular therapy with tumor-infiltrating lymphocytes (TIL-ACT) represents a promising immunotherapy alternative to immune checkpoint blockade, particularly in certain patients with advanced melanoma. Using single-cell transcriptomics and spatial proteomics, Barras et al. analyzed tumor specimens from patients with metastatic melanoma receiving ex vivo–expanded TIL-ACT through a phase 1 clinical trial. At baseline, tumors responding to TIL-ACT had more activated T cells, macrophages, and dendritic cells, which formed strong stimulatory interactions in responding tumors. After TIL-ACT, responders showed reprograming of myeloid cells including toward CXCL9⁺ macrophages and further expansion of T-myeloid cell networks. Together, these findings demonstrate that robust baseline supporting networks between intratumoral immune cells are strongly associated with response to TIL-ACT in metastatic melanoma. —Claire Olingy [ABSTRACT FROM AUTHOR]

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