Abstract 4007: The cellular architecture of the infused T cell predicts efficacy of autologous tumor-infiltrating lymphocyte therapy (LM-103) in acral melanoma

Abstract Acral melanoma (AM), the predominant melanoma subtype in Asia, shows poor response to immune checkpoint inhibitors, underscoring the need for alternative immunotherapies. An investigator-initiated trial evaluates autologous tumor-infiltrating lymphocyte (TIL) therapy (LM-103) in four Chinese patients with advanced AM, achieving a 75% disease control rate and one durable complete response. To define determinants of therapeutic outcome, integrated single-cell RNA sequencing (scRNA-seq) and T-cell receptor sequencing (TCR-seq) are performed on infused TIL products, tumors, and longitudinal peripheral blood. Single-cell profiling reveals marked heterogeneity within the infused products, including naïve, regulatory, follicular helper (Tfh), cytotoxic, and multiple exhausted T-cell states. Responders demonstrate striking enrichment of Tfh and intermediate exhausted (TEXᵢnt) CD8+ T cells, whereas the non-responder product is dominated by terminally exhausted subsets. Pseudotime analysis supports a conserved exhaustion continuum in which TEXᵢnt cells occupy a plastic, functionally competent intermediate state. Cell-cell communication modeling shows that responder products contain a densely connected signaling ecosystem driven by Tfh- and TEXᵢnt-mediated costimulatory pathways, such as CD40, CD70, and FASLG. In contrast, non-responder products exhibit sparse, immunosuppressive networks dominated by TGFβ and MIF signaling. TCR integration demonstrates higher clonality within Tfh and TEXᵢnt subsets in responders. Longitudinal tracking reveals that the complete responder maintains stable high clonality after infusion. Notably, a dominant clonotype enriched in the TEXᵢnt population of the infused product persists in peripheral blood and later adopts a progenitor-like exhausted (TEXₚrog) state. This finding provides direct in vivo evidence that intermediate exhausted T cells can differentiate into a progenitor-like state after adoptive transfer, establishing a durable, self-renewing reservoir capable of sustaining long-term anti-tumor immunity. These results define the cellular and clonal architecture underlying successful TIL therapy in AM. Durable benefit is determined not by the size of the infused product but by the presence and persistence of coordinated Tfh-TEXᵢnt ecosystems that seed long-lived progenitor-like immunity. These insights offer mechanistic biomarkers and provide a foundation for optimizing TIL manufacturing for melanoma subtypes refractory to current immunotherapies. Citation Format: Chao Zhang, Jilong Yang, Xiangchun Li, Kexin Chen, Hongru Shen. The cellular architecture of the infused T cell predicts efficacy of autologous tumor-infiltrating lymphocyte therapy (LM-103) in acral melanoma abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts) ; 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86 (7 Suppl): Abstract nr 4007.