Newly emerged immunogenic neoantigens in established tumors enable hosts to regain immunosurveillance in a T-cell-dependent manner.
Animals
Antigens, Neoplasm
/ immunology
B7-H1 Antigen
/ antagonists & inhibitors
CD8-Positive T-Lymphocytes
/ immunology
Cell Line, Tumor
Chickens
Colonic Neoplasms
/ immunology
Doxycycline
/ pharmacology
Drug Resistance, Neoplasm
/ drug effects
Female
Humans
Immune Checkpoint Inhibitors
/ pharmacology
Melanoma, Experimental
/ immunology
Membrane Proteins
/ immunology
Mice
Mice, Inbred BALB C
Mice, Inbred C57BL
Mice, Nude
Monitoring, Immunologic
Ovalbumin
/ immunology
Programmed Cell Death 1 Receptor
/ antagonists & inhibitors
Tumor Escape
/ immunology
PD-1/PD-L1 blockade
mouse tumor models
neoantigens
tumor immunology
Journal
International immunology
ISSN: 1460-2377
Titre abrégé: Int Immunol
Pays: England
ID NLM: 8916182
Informations de publication
Date de publication:
01 01 2021
01 01 2021
Historique:
received:
17
06
2020
accepted:
25
07
2020
pubmed:
31
7
2020
medline:
10
2
2022
entrez:
31
7
2020
Statut:
ppublish
Résumé
Tumor neoantigens derived from genetic alterations are potential T-cell targets for antitumor immunity. However, tumors develop immune escape mechanisms including loss of preexisting neoantigens and/or impairment of T-cell responses during tumor development and progression. Here, we addressed whether newly emerged immunogenic neoantigens in established tumors enabled hosts to inhibit tumor growth via controlling immune escape mechanisms. Using a doxycycline-driven gene expression system, we generated murine MC38, CT26 (colorectal cancer) and B16 (melanoma) cell lines with inducible expression of model immunogenic neoantigens such as chicken ovalbumin and human NY-ESO-1. A model neoantigen was induced by doxycycline administration in the tumors once tumors became palpable. Tumor growth was significantly inhibited upon induction of the neoantigen and this inhibition was abrogated in nude mice lacking T cells and in mice deprived of CD8+ T cells, indicating the critical role of CD8+ T cells in tumor regression. In addition, PD-1/PD-L1 blockade further augmented the antitumor immune response, resulting in a far stronger inhibition of tumor growth. Accordingly, newly emerged tumor neoantigen-specific CD8+ T cells with enhanced effector functions were significantly increased in mice treated with PD-1/PD-L1 blockade. We propose that a newly emerged neoantigen is sufficient to inhibit tumor growth via preventing immune escape in a T-cell-dependent manner. Our results imply that induction of immunogenic tumor neoantigens is a novel strategy to overcome the resistance to immune checkpoint blockade therapy.
Identifiants
pubmed: 32729901
pii: 5878926
doi: 10.1093/intimm/dxaa049
doi:
Substances chimiques
Antigens, Neoplasm
0
B7-H1 Antigen
0
CTAG1B protein, human
0
Cd274 protein, mouse
0
Immune Checkpoint Inhibitors
0
Membrane Proteins
0
Pdcd1 protein, mouse
0
Programmed Cell Death 1 Receptor
0
Ovalbumin
9006-59-1
Doxycycline
N12000U13O
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
39-48Informations de copyright
© The Japanese Society for Immunology. 2020. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.