Neoantigen-reactive CD8+ T cells affect clinical outcome of adoptive cell therapy with tumor-infiltrating lymphocytes in melanoma
(2022) In Journal of Clinical Investigation 132(2).- 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... (More)
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.
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- author
- organization
- publishing date
- 2022-01
- type
- Contribution to journal
- publication status
- published
- subject
- in
- Journal of Clinical Investigation
- volume
- 132
- issue
- 2
- article number
- 150535
- publisher
- The American Society for Clinical Investigation
- external identifiers
-
- scopus:85123651400
- pmid:34813506
- ISSN
- 0021-9738
- DOI
- 10.1172/JCI150535
- language
- English
- LU publication?
- yes
- id
- bb69713f-ca0a-496f-8bdf-6f82bd1d789c
- date added to LUP
- 2022-04-11 11:46:54
- date last changed
- 2024-06-16 12:50:52
@article{bb69713f-ca0a-496f-8bdf-6f82bd1d789c,
abstract = {{<p>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.</p>}},
author = {{Kristensen, Nikolaj Pagh and Heeke, Christina and Tvingsholm, Siri A. and Borch, Annie and Draghi, Arianna and Crowther, Michael D. and Carri, Ibel and Munk, Kamilla K. and Holm, Jeppe Sejerø and Bjerregaard, Anne Mette and Bentzen, Amalie Kai and Marquard, Andrea M. and Szallasi, Zoltan and McGranahan, Nicholas and Andersen, Rikke and Nielsen, Morten and Jönsson, Göran B. and Donia, Marco and Svane, Inge Marie and Hadrup, Sine Reker}},
issn = {{0021-9738}},
language = {{eng}},
number = {{2}},
publisher = {{The American Society for Clinical Investigation}},
series = {{Journal of Clinical Investigation}},
title = {{Neoantigen-reactive CD8<sup>+</sup> T cells affect clinical outcome of adoptive cell therapy with tumor-infiltrating lymphocytes in melanoma}},
url = {{http://dx.doi.org/10.1172/JCI150535}},
doi = {{10.1172/JCI150535}},
volume = {{132}},
year = {{2022}},
}