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

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

Journal of Clinical Investigation

Journal of Clinical Investigation

Lugar: Ann Arbor; Año: 2022 vol. 132

BACKGROUND. Neoantigen-driven recognition and T cell?mediated killing contribute to tumor clearance following adoptivecell therapy (ACT) with tumor-infiltrating lymphocytes (TILs). Yet how diversity, frequency, and persistence of expandedneoepitope-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 inTIL 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 withprogressive disease outcome. Moreover, we found that the frequency of neoepitope-specific CD8+ T cells in TIL infusionproducts correlated with increased survival and that neoepitope-specific CD8+ T cells shared with the infusion product inposttreatment blood samples were unique to responders of TIL-ACT. Finally, we found that a transcriptional signature forlymphocyte 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 thatsuccessful TIL-ACT is associated with an expansion of neoepitope-specific CD8+ T cells.