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 Research and Public Health Immunology

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 1

Detection of neoepitope-specific CD8+ T cells in expanded TILs of melanoma.

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Detection of neoepitope-specific CD8+ T cells in expanded TILs of melano...
(A) Melanoma-specific mutation-derived peptides were predicted to bind patient’s HLA molecules using the prediction platform MuPeXI. DNA barcode–labeled MHC multimers with either neopeptides or virus-derived peptides were assembled on a PE-labeled streptavidin-conjugated dextran backbone. Multimer-binding NARTs were fluorescence sorted and T cell specificities decoded by barcode sequencing. (B) Examples of neoepitope- and virus-specific CD8+ T cells detected in expanded TILs of melanoma patient M22 (PR) across available HLAs. Significant barcode enrichment is defined based on a log2 FC of the number of barcode reads compared with triplicate baseline samples. P ≤ 0.001 (egdeR) after correction for multiple hypothesis testing (see Methods). Blue, NARTs; red, virus-specific CD8+ T cells; black, multimers with nonenriched barcodes. V17 annotate EBV peptide RAKFKQLL. (C) Number and frequency of neoepitope- and virus-specific CD8+ T cells in TIL samples across cohort of 26 melanoma patients. Blue, NARTs; red, virus-specific CD8+ T cells. Number of and frequency of NARTs were normalized to absolute HLA coverage (see Methods). Sum est. frequency, sum of estimate frequency.