Pagh Kristensen, Heeke, and Tvingsholm et al. investigated the neoepitope specificity of tumor-infiltrating lymphocytes in adoptive cell transfer (TIL-ACT) products in 26 patients with metastatic melanoma. Using 5921 barcoded pMHC multimers, 106 CD8+ TIL-ACT recognizing patient-specific neoepitopes (neoantigen-reactive T cells [NARTs]) were detected. NARTs were more diverse and frequent in responders to ACT, NART diversity and frequency correlated with progression-free survival, and NARTs persisted in the periphery of responders. High NART frequency was associated with humoral and B cell-mediated mechanisms and immune signaling pathway gene signatures.
Contributed by Maartje Wouters
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.
Author Info: (1) Department of Health Technology, Technical University of Denmark (DTU), Kgs. Lyngby, Denmark. (2) Department of Health Technology, Technical University of Denmark (DTU), Kgs. L
Author Info: (1) Department of Health Technology, Technical University of Denmark (DTU), Kgs. Lyngby, Denmark. (2) Department of Health Technology, Technical University of Denmark (DTU), Kgs. Lyngby, Denmark. (3) Department of Health Technology, Technical University of Denmark (DTU), Kgs. Lyngby, Denmark. (4) Department of Health Technology, Technical University of Denmark (DTU), Kgs. Lyngby, Denmark. (5) Department of Oncology, Copenhagen University Hospital, Herlev, Denmark. (6) Department of Oncology, Copenhagen University Hospital, Herlev, Denmark. (7) Instituto de Investigaciones Biotecnolgicas, Universidad Nacional de San Martn, Buenos Aires, Argentina. (8) Department of Health Technology, Technical University of Denmark (DTU), Kgs. Lyngby, Denmark. (9) Department of Health Technology, Technical University of Denmark (DTU), Kgs. Lyngby, Denmark. (10) Department of Health Technology, Technical University of Denmark (DTU), Kgs. Lyngby, Denmark. (11) Department of Health Technology, Technical University of Denmark (DTU), Kgs. Lyngby, Denmark. (12) Department of Health Technology, Technical University of Denmark (DTU), Kgs. Lyngby, Denmark. (13) Danish Cancer Society Research Center, Danish Cancer Society, Copenhagen, Denmark. (14) Cancer Institute, University College London, London, United Kingdom. (15) Department of Oncology, Copenhagen University Hospital, Herlev, Denmark. (16) Section for Bioinformatics, Department of Health Technology, Technical University of Denmark (DTU), Kgs. Lyngby, Denmark. (17) Department of Clinical Sciences, Lund University, Lund, Sweden. (18) Department of Oncology, Copenhagen University Hospital, Herlev, Denmark. (19) Department of Oncology, Copenhagen University Hospital, Herlev, Denmark. (20) Department of Health Technology, Technical University of Denmark (DTU), Kgs. Lyngby, Denmark.
