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 2

Autologous tumor recognition by enriched NARTs.

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Autologous tumor recognition by enriched NARTs. (A) Correlation of TIL r...
(A) Correlation of TIL reactivity to autologous tumor (measured by intracellular cytokine staining) and sum of estimated NART frequency. TIL reactivity toward an autologous tumor cell line was defined as positive for 2 out of the 3 proteins TNF-α, IFN-γ, and CD107a. Sixteen patients with available tumor reactivity data were included from both responder (n = 6) and nonresponders (n = 10). R and P values from Spearman’s correlation with 95% CIs in gray. NART frequency was normalized to absolute HLA coverage (see Methods). (B and C) HLA-B*08:01–restricted, NLFR-specific CD8+ T cells from M22 TIL Inf product were sorted based on 2-color tetramer binding (B) and expanded in vitro followed by NLFR-tetramer staining (C). (D) Tumor reactivity as measured by TNF-α/IFN-γ release after coculture of expanded, NART-specific cell products with or without autologous tumor cell lines, with PMA/ionomycin or with autologous tumor cell line and IFN-γ. NLFR, NLFRRVWEL from USP34S1391F. TIL reactivity data shown in A originate from previous study (4), and the assay was performed as described previously (66).