Neoantigen-reactive CD8+ T cells affect clinical outcome of adoptive cell therapy with tumor-infiltrating lymphocytes in melanoma
Nikolaj Pagh Kristensen, … , Inge Marie Svane, Sine Reker Hadrup
Nikolaj Pagh Kristensen, … , Inge Marie Svane, Sine Reker Hadrup
Published November 23, 2021
Citation Information: J Clin Invest. 2022;132(2):e150535. https://doi.org/10.1172/JCI150535.
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Clinical Medicine Immunology Therapeutics

Neoantigen-reactive CD8+ T cells affect clinical outcome of adoptive cell therapy with tumor-infiltrating lymphocytes in melanoma

Abstract

BACKGROUND Neoantigen-driven recognition and T cell–mediated killing contribute to tumor clearance following adoptive cell therapy (ACT) with tumor-infiltrating lymphocytes (TILs). Yet how diversity, frequency, and persistence of expanded neoepitope-specific CD8+ T cells derived from TIL infusion products affect patient outcome is not fully determined.METHODS Using barcoded pMHC multimers, we provide a comprehensive mapping of CD8+ T cells recognizing neoepitopes in TIL infusion products and blood samples from 26 metastatic melanoma patients who received ACT.RESULTS We identified 106 neoepitopes within TIL infusion products corresponding to 1.8% of all predicted neoepitopes. We observed neoepitope-specific recognition to be virtually devoid in TIL infusion products given to patients with progressive disease outcome. Moreover, we found that the frequency of neoepitope-specific CD8+ T cells in TIL infusion products correlated with increased survival and that neoepitope-specific CD8+ T cells shared with the infusion product in posttreatment blood samples were unique to responders of TIL-ACT. Finally, we found that a transcriptional signature for lymphocyte activity within the tumor microenvironment was associated with a higher frequency of neoepitope-specific CD8+ T cells in the infusion product.CONCLUSIONS These data support previous case studies of neoepitope-specific CD8+ T cells in melanoma and indicate that successful TIL-ACT is associated with an expansion of neoepitope-specific CD8+ T cells.FUNDING NEYE Foundation; European Research Council; Lundbeck Foundation Fellowship; Carlsberg Foundation.

Authors

Nikolaj Pagh Kristensen, Christina Heeke, Siri A. Tvingsholm, Annie Borch, Arianna Draghi, Michael D. Crowther, Ibel Carri, Kamilla K. Munk, Jeppe Sejerø Holm, Anne-Mette Bjerregaard, Amalie Kai Bentzen, Andrea M. Marquard, Zoltan Szallasi, Nicholas McGranahan, Rikke Andersen, Morten Nielsen, Göran B. Jönsson, Marco Donia, Inge Marie Svane, Sine Reker Hadrup

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Figure 6

Characteristics of immunogenic neoepitopes.

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Characteristics of immunogenic neoepitopes. (A) Venn diagram of 5921 uni...
(A) Venn diagram of 5921 unique pMHC; 204 immunogenic and 5717 nonimmunogenic as determined by the presence of neoepitope-specific CD8+ T cells in patients at any time. The distribution and overlap of immunogenic versus nonimmunogenic neoepitopes deriving from either cancer-driver genes (6.5% versus. 3.3%, P = 0.0048, z test), C/T mutations (3.4% versus. 3.5%, P = 0.78, z test), or clonal mutations (80.1% versus 86.0% P = 0.03, z test). Clonality could not be determined for 913 neopeptides, as WES was performed on autologous tumor cell lines (M22, M24, and a subset of M15). These were excluded from the z test, but included in the Venn diagram as subclonal mutations for visualization. (B) Eluted ligand (EL) percentage rank score of mutated peptide compared with percentage rank score of the corresponding germline peptide without mutation or nearest germline peptide. Red, immunogenic peptides. 3.4% CB versus 3.5 % IB, P = 0.99, z test. (C) Mutant EL percentage rank score comparing proportion of immunogenic neoepitopes above and below 0.5 percentage rank score (3.3 % versus 3.5, P = 0.71, z test). (D) RNA expression (TPM) comparing proportion of immunogenic peptides with expression above and below 2 TPM (4.2 % versus. 2.6%, P = 0.001, z test). (E) Unsupervised clustering of the 226 differentially expressed gene according to high and low sum of estimated frequency within TIL Inf products split by the median frequency (0.63%). Denoted names were prioritized according to GO terms and known function. (F) Enriched GO gene set representing lymphocyte-mediated immunity. (G) Enriched GO gene set representing T cell proliferation. Significance threshold or GSEA was set at FDR ≤ 0.01. M24 was excluded from D–G, as RNA-Seq data were obtained from an autologous tumor cell line. n = 25. M22 was included in D–G using data from the tumor biopsy used for manufacturing of the infusion product.