Neoantigen-reactive CD8+ T cells affect clinical outcome of adoptive transfer with tumor-infiltrating lymphocytes in melanoma.
Kristensen, N. P., Heeke, C., Tvingsholm, S. A., Borch, A., Draghi, A., Crowther, M. D., Carri, I., Munk, K. K., Holm, J. S., Bjerregaard, A. M., Bentzen, A. K., Marquard, A. M., Szallasi, Z., McGranahan, N., Andersen, R., Nielsen, M., Jonsson, G. B., Donia, M., Svane, I. M. and Hadrup, S. R.
Department of Health Technology, Technical University of Denmark (DTU), Kgs. Lyngby, Denmark.
Department of Oncology, Copenhagen University Hospital, Herlev, Denmark.
Instituto de Investigaciones Biotecnologicas, Universidad Nacional de San Martin, Buenos Aires, Argentina.
Danish Cancer Society Research Center, Danish Cancer Society, Copenhagen, Denmark.
Cancer Institute, University College London, London, United Kingdom.
Section for Bioinformatics, Department of Health Technology, Technical University of Denmark (DTU), Kgs. Lyngby, Denmark.
Department of Clinical Sciences, Lund University, Lund, Sweden.
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.
Journal of Clinical Investigation 132(2): en prensa (2022)