학술논문
Neoantigen-reactive CD8+ T cells affect clinical outcome of adoptive cell therapy with tumor-infiltrating lymphocytes in melanoma.
Document Type
Journal Article
Author
Kristensen, Nikolaj Pagh; Heeke, Christina; Tvingsholm, Siri A.; Borch, Annie; Draghi, Arianna; Crowther, Michael D.; Carri, Ibel; Munk, Kamilla K.; Holm, Jeppe Sejerø; Bjerregaard, Anne-Mette; Bentzen, Amalie Kai; Marquard, Andrea M.; Szallasi, Zoltan; McGranahan, Nicholas; Andersen, Rikke; Nielsen, Morten; Jönsson, Göran B.; Donia, Marco; Svane, Inge Marie; Hadrup, Sine Reker
Source
Subject
*T cells
*MELANOMA
*TUMOR-infiltrating immune cells
*CD8 antigen
*CELLULAR therapy
*BLOOD products
*MELANOMA treatment
*IMMUNIZATION
*IMMUNOLOGY technique
*LYMPHOCYTES
*TUMOR antigens
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Language
ISSN
0021-9738
Abstract
BACKGROUNDNeoantigen-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.METHODSUsing 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.RESULTSWe 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.CONCLUSIONSThese 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.FUNDINGNEYE Foundation; European Research Council; Lundbeck Foundation Fellowship; Carlsberg Foundation. [ABSTRACT FROM AUTHOR]