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- W2891145057 abstract "3047 Background: Many patients that initially respond to cancer immunotherapy with adoptive cell therapy (ACT) using T cell receptor (TCR) engineered autologous T cells eventually develop resistance and experience relapse (termed acquired resistance) through mechanisms that remain poorly understood. Methods: We analyzed baseline and on-therapy tumor samples from 15 patients with metastatic melanoma that were treated with transgenic lymphocytes expressing a MART-1 TCR administered with a MART-1 peptide-pulsed dendritic cell vaccine. We studied in vitro the effect of inflammatory mediators and MART-1-specific T cells on human patient-derived melanoma cell lines, and performed bulk RNA-sequencing and methylation analysis of melanosome genes to gain further insight into mechanisms of acquired immunotherapy resistance in these cells. Results: Progression biopsies of metastatic melanoma lesions in one of the patients demonstrated phenotypic dedifferentiation as a resistance mechanism to ACT, a phenomenon previously only reported in murine models (Landsberg et al., Nature, 2012). After a three month period of tumor regression, the patient presented in relapse with tumors lacking melanocytic antigens (MART-1, gp100) but expressing the inflammation-induced neural crest marker NGFR (or CD271). We validated inflammation-induced tumor dedifferentiation of 8 melanoma cell lines in vitro after stimulation with TNFa for 3 days, and identified gene pathways altered in dedifferentiated cells by RNA-sequencing. Gene set enrichment analysis revealed that TNFa treatment enriched for genes involved in epithelial to mesenchymal transition (NES = 1.92, FDR < 0.001) and neural crest stem cell identity (NES = 1.49, FDR = 0.016), and pathways in the innate anti-PD-1 resistance signature (IPRES). TNFa treatment also downregulated genes in the MITF pathway (NES = -2.38, FDR < 0.001). Conclusions: Inflammation-induced dedifferentiation is a new mechanism that can lead to acquired resistance to cancer immunotherapy." @default.
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- W2891145057 date "2018-05-20" @default.
- W2891145057 modified "2023-10-18" @default.
- W2891145057 title "Acquired resistance to T cell adoptive transfer by inflammation-induced melanoma dedifferentiation." @default.
- W2891145057 doi "https://doi.org/10.1200/jco.2018.36.15_suppl.3047" @default.
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