Targeting resistance to radiation-immunotherapy in cold HNSCCs by modulating the Treg-dendritic cell axis.
Animals
Antineoplastic Agents, Immunological
/ pharmacology
Basic-Leucine Zipper Transcription Factors
/ genetics
Cell Line, Tumor
Combined Modality Therapy
Dendritic Cells
/ drug effects
Drug Resistance, Neoplasm
Head and Neck Neoplasms
/ immunology
Immune Checkpoint Inhibitors
/ pharmacology
Immunotherapy
Interleukin-2 Receptor alpha Subunit
/ antagonists & inhibitors
Lymphocyte Depletion
Mice, Inbred BALB C
Mice, Inbred C57BL
Mice, Knockout
Phenotype
Radiation Dose Hypofractionation
Radiation Tolerance
Repressor Proteins
/ genetics
Squamous Cell Carcinoma of Head and Neck
/ immunology
T-Lymphocytes, Regulatory
/ drug effects
Tumor Burden
Tumor Microenvironment
Tumor Necrosis Factor Receptor Superfamily, Member 9
/ antagonists & inhibitors
costimulatory and inhibitory t-cell receptors
dendritic cells
head and neck neoplasms
radioimmunotherapy
t-lymphocytes
Journal
Journal for immunotherapy of cancer
ISSN: 2051-1426
Titre abrégé: J Immunother Cancer
Pays: England
ID NLM: 101620585
Informations de publication
Date de publication:
04 2021
04 2021
Historique:
accepted:
10
01
2021
entrez:
22
4
2021
pubmed:
23
4
2021
medline:
18
12
2021
Statut:
ppublish
Résumé
Numerous trials combining radiation therapy (RT) and immunotherapy in head and neck squamous cell carcinoma (HNSCC) are failing. Using preclinical immune cold models of HNSCC resistant to RT-immune checkpoint inhibitors, we investigate therapeutic approaches of overcoming such resistance by examining the differential microenvironmental response to RT. We subjected two HPV-negative orthotopic mouse models of HNSCC to combination RT, regulatory T cells (Treg) depletion, and/or CD137 agonism. Tumor growth was measured and intratumorous and lymph node immune populations were compared among treatment groups. Human gene sets, genetically engineered mouse models In MOC2 orthotopic tumors, we find no therapeutic benefit to targeting classically defined immunosuppressive myeloids, which increase with RT. In these radioresistant tumors, supplementing combination RT and Treg depletion with anti-CD137 agonism stimulates CD103 Regulating Treg functionality and DC activation status within the lymph node is critical for generating a T cell effector response in these highly radioresistant tumors. These findings underscore the plasticity of Tregs and represent a new therapeutic opportunity for reprogramming the tumor microenvironment in HNSCCs resistant to conventional radioimmunotherapy approaches.
Sections du résumé
BACKGROUND
Numerous trials combining radiation therapy (RT) and immunotherapy in head and neck squamous cell carcinoma (HNSCC) are failing. Using preclinical immune cold models of HNSCC resistant to RT-immune checkpoint inhibitors, we investigate therapeutic approaches of overcoming such resistance by examining the differential microenvironmental response to RT.
METHODS
We subjected two HPV-negative orthotopic mouse models of HNSCC to combination RT, regulatory T cells (Treg) depletion, and/or CD137 agonism. Tumor growth was measured and intratumorous and lymph node immune populations were compared among treatment groups. Human gene sets, genetically engineered mouse models
RESULTS
In MOC2 orthotopic tumors, we find no therapeutic benefit to targeting classically defined immunosuppressive myeloids, which increase with RT. In these radioresistant tumors, supplementing combination RT and Treg depletion with anti-CD137 agonism stimulates CD103
CONCLUSIONS
Regulating Treg functionality and DC activation status within the lymph node is critical for generating a T cell effector response in these highly radioresistant tumors. These findings underscore the plasticity of Tregs and represent a new therapeutic opportunity for reprogramming the tumor microenvironment in HNSCCs resistant to conventional radioimmunotherapy approaches.
Identifiants
pubmed: 33883256
pii: jitc-2020-001955
doi: 10.1136/jitc-2020-001955
pmc: PMC8061827
pii:
doi:
Substances chimiques
Antineoplastic Agents, Immunological
0
Basic-Leucine Zipper Transcription Factors
0
Il2ra protein, mouse
0
Immune Checkpoint Inhibitors
0
Interleukin-2 Receptor alpha Subunit
0
Repressor Proteins
0
SNFT protein, mouse
0
Tnfrsf9 protein, mouse
0
Tumor Necrosis Factor Receptor Superfamily, Member 9
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : NIAID NIH HHS
ID : R01 AI121209
Pays : United States
Organisme : NIAID NIH HHS
ID : R01 AI155474
Pays : United States
Organisme : NIDDK NIH HHS
ID : R01 DK125595
Pays : United States
Organisme : NCI NIH HHS
ID : P30 CA046934
Pays : United States
Organisme : NIDCR NIH HHS
ID : R01 DE028529
Pays : United States
Organisme : NIDCR NIH HHS
ID : R01 DE028282
Pays : United States
Informations de copyright
© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.
Déclaration de conflit d'intérêts
Competing interests: No, there are no competing interests.
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