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

Kristensen, NP; Heeke, C; Tvingsholm, SA; Borch, A; Draghi, A; Crowther, MD; Carri, I; ... Hadrup, SR; + view all (2021) Neoantigen-reactive CD8+ T cells affect clinical outcome of adoptive transfer with tumor-infiltrating lymphocytes in melanoma. Journal of Clinical Investigation 10.1172/JCI150535. (In press). Green open access

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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 mela-noma 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 in-creased survival, and that detection of engrafted CD8+ T cells in post-treatment (i.e. originating from the TIL infusion product) 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.

Type: Article
Title: Neoantigen-reactive CD8+ T cells affect clinical outcome of adoptive transfer with tumor-infiltrating lymphocytes in melanoma
Location: United States
Open access status: An open access version is available from UCL Discovery
DOI: 10.1172/JCI150535
Publisher version: https://doi.org/10.1172/JCI150535
Language: English
Additional information: This version is the version of record. For information on re-use, please refer to the publisher's terms and conditions.
Keywords: Cancer immunotherapy, Immunology, Melanoma, T cells, Therapeutics
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute > Research Department of Oncology
URI: https://discovery.ucl.ac.uk/id/eprint/10139296
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