Year: 2026
Type: conference-abstract
Abstract: Background Adoptive transfer of tumor-infiltrating lymphocytes (TIL) can induce durable responses in melanoma, yet most patients experience incomplete or transient benefit. The mechanisms of acquired resistance - particularly how cancer-intrinsic evolution subverts TIL efficacy - remain poorly defined.Methods To examine tumor heterogeneity, we leveraged a rare longitudinal single-cell atlas from a mucosal melanoma patient, capturing the tumor ecosystem at harvest and progression alongside the matched TIL infusion product. To bridge phenotypical observations to functional mechanisms, we established five patient-derived cancer cell lines from pre-treatment (lymph node) and post-treatment (primary site) biopsies. To nominate key molecules mediating resistance, we leveraged bulk RNA-seq data from these pre- and post-treatment cancer cell lines, with or without cytokine (IFNγ and LTα/β) treatment, alongside the corresponding scRNA-seq data from the TIL infusion product. To dissect the mechanisms of resistance, we utilized genetic perturbations and pharmacological inhibitors.Results We identified widespread variation across different tumor regions and timepoints within the tumor microenvironment and transcriptionally distinct malignant subpopulations, with specific cancer cell states emerging or becoming enriched at the primary site after TIL therapy. We showed that the established cancer cell lines recapitulate the in situ phenotype, with the post-cancer cell line (from the primary site) being less sensitive to the TIL infusion product and cytokines. LGALS3BP is highly expressed in the post-cancer cell line and is inducible by TIL-derived cytokines (IFNγ and LTα/β), while its receptors (e.g., LGALS3) are upregulated on the infused TIL product. Knockout of LGALS3BP or LGALS3 in cancer cells or TIL, respectively, enhances TIL-mediated cancer cell killing.Conclusions Here, we uncover a novel cancer-intrinsic resistance mechanism to TIL therapy. Our findings demonstrate that LGALS3BP is a dual-function regulator that promotes tumor fitness and TIL resistance through both intracellular survival signaling and paracrine immune suppression. These results not only provide mechanistic insights into the role of the LGALS3BP/LGALS3 axis in driving the resistance to TIL therapy but also potentially inform the next generation of personalized immunotherapeutic strategies.Ethics Approval Ethics approval was obtained for this study. Tumour samples were collected and analysed according to Dana-Farber/Harvard Cancer Center IRB-approved protocols (DF/HCC 11-181).
Language: English
Subfield: Oncology
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $2,490
OpenAlex ID: W7225197742