Pre-treatment tumor neo-antigen responses in draining lymph nodes are infrequent but predict checkpoint blockade therapy outcome.
Neo-antigen
T cells
biomarker
checkpoint blockade
mesothelioma
Journal
Oncoimmunology
ISSN: 2162-4011
Titre abrégé: Oncoimmunology
Pays: United States
ID NLM: 101570526
Informations de publication
Date de publication:
2020
2020
Historique:
received:
11
09
2019
revised:
20
10
2019
accepted:
22
10
2019
entrez:
1
2
2020
pubmed:
1
2
2020
medline:
1
2
2020
Statut:
epublish
Résumé
Immune checkpoint blockade (ICPB) is a powerfully effective cancer therapy in some patients. Tumor neo-antigens are likely main targets for attack but it is not clear which and how many tumor mutations in individual cancers are actually antigenic, with or without ICPB therapy and their role as neo-antigen vaccines or as predictors of ICPB responses. To examine this, we interrogated the immune response to tumor neo-antigens in a murine model in which the tumor is induced by a natural human carcinogen (i.e. asbestos) and mimics its human counterpart (i.e. mesothelioma). We identified and screened 33 candidate neo-antigens, and found T cell responses against one candidate in tumor-bearing animals, mutant UQCRC2. Interestingly, we found a high degree of inter-animal variation in the magnitude of neo-antigen responses in otherwise identical mice. ICPB therapy with Cytotoxic T-lymphocyte-associated protein (CTLA-4) and α-glucocorticoid-induced TNFR family related gene (GITR) in doses that induced tumor regression, increased the magnitude of responses and unmasked functional T cell responses against another neo-antigen, UNC45a. Importantly, the magnitude of the pre-treatment draining lymph node (dLN) response to UNC45a closely corresponded to ICPB therapy outcomes. Surprisingly however, boosting pre-treatment UNC45a-specific T cell numbers did not improve response rates to ICPB. These observations suggest a novel biomarker approach to the clinical prediction of ICPB response and have important implications for the development of neo-antigen vaccines.
Identifiants
pubmed: 32002299
doi: 10.1080/2162402X.2019.1684714
pii: 1684714
pmc: PMC6959436
doi:
Substances chimiques
Antigens, Neoplasm
0
Cancer Vaccines
0
Immune Checkpoint Inhibitors
0
Intracellular Signaling Peptides and Proteins
0
UNC45A protein, human
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Pagination
1684714Informations de copyright
© 2019 The Author(s). Published with license by Taylor & Francis Group, LLC.
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