Neoantigen-reactive CD8+ T cells affect clinical outcome of adoptive cell therapy with tumor-infiltrating lymphocytes in melanoma
Nikolaj Pagh Kristensen, … , Inge Marie Svane, Sine Reker Hadrup
Nikolaj Pagh Kristensen, … , Inge Marie Svane, Sine Reker Hadrup
Published November 23, 2021
Citation Information: J Clin Invest. 2022;132(2):e150535. https://doi.org/10.1172/JCI150535.
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Clinical Research and Public Health Immunology

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

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 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 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.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.

Authors

Nikolaj Pagh Kristensen, Christina Heeke, Siri A. Tvingsholm, Annie Borch, Arianna Draghi, Michael D. Crowther, Ibel Carri, Kamilla K. Munk, Jeppe Sejerø Holm, Anne-Mette Bjerregaard, Amalie Kai Bentzen, Andrea M. Marquard, Zoltan Szallasi, Nicholas McGranahan, Rikke Andersen, Morten Nielsen, Göran B. Jönsson, Marco Donia, Inge Marie Svane, Sine Reker Hadrup

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Figure 5

Responding patients have high-frequency engrafting NARTs in their TIL Inf product.

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Responding patients have high-frequency engrafting NARTs in their TIL In...
(A and B) Each NART population was annotated and colored according to first appearance in pre-ACT PBMCs, TIL Inf products, and post-ACT PBMCs (<1 month to <48 months). Black numbers specify the total number of NARTs detected for the specific time and RECIST group. (A) Distribution of NARTs within RECIST groups according to first appearance. (B) Distribution of NART frequency within RECIST groups according to first appearance. *M01 (CR) did not have pre-ACT and <1 month PBMCs available and was excluded from analysis to avoid a biased distribution. **Frequency data could not be calculated for M40 pre-ACT and M40 post-ACT <1 month, which were excluded (see Methods). (C) Venn diagram showing the overlap of detected NARTs among pre-ACT PBMCs, TIL Inf products, and all post-ACT PBMC samples. n = 19. (D) The estimated frequency of each NART population detected less than 1 month after infusion. Responses were either regarded as engrafted (i.e., also detected in TIL Inf) or novel. n = 16. M01 and M40 were excluded as stated for A and B; M29 did not have detectable antigen-specific CD8+ T cells before the second time point after ACT. (E) The estimated frequency of each NART population observed in TIL Inf products. Nonengrafted versus engrafted (i.e., detected at least once at a later time points). n = 19. (F and G) Number and frequency of engrafted NARTs, defined by presence in both TIL Inf product and after TIL-ACT. n varied according to sample availability (Supplemental Table 1 and Supplemental Figure 8). M40 before ACT and <1 month PBMCs were excluded from G (see Methods). Sum of estimated frequency in G was increased by 0.01 to account for 0 values. P values from Mann-Whitney U test. Whiskers represent IQR.