Complement C3a and C5a receptor blockade modulates regulatory T cell conversion in head and neck cancer.
Animals
Cell Line, Tumor
Cell Proliferation
/ drug effects
Complement C3
/ genetics
Complement Inactivating Agents
/ toxicity
Dexamethasone
/ toxicity
Forkhead Transcription Factors
/ metabolism
Head and Neck Neoplasms
/ genetics
Humans
Lymphocytes, Tumor-Infiltrating
/ drug effects
Mice, Inbred BALB C
Mice, Inbred C57BL
Mice, Knockout
Receptor, Anaphylatoxin C5a
/ antagonists & inhibitors
Receptors, Complement
/ antagonists & inhibitors
Signal Transduction
Squamous Cell Carcinoma of Head and Neck
/ genetics
T-Lymphocytes, Regulatory
/ drug effects
Time Factors
Tumor Burden
/ drug effects
T-lymphocytes
immunotherapy
radiotherapy
tumor microenvironment
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:
03 2021
03 2021
Historique:
accepted:
09
03
2021
entrez:
1
4
2021
pubmed:
2
4
2021
medline:
18
12
2021
Statut:
ppublish
Résumé
Resistance to therapy is a major problem in treating head and neck squamous cell carcinomas (HNSCC). Complement system inhibition has been shown to reduce tumor growth, metastasis, and therapeutic resistance in other tumor models, but has yet to be explored in the context of HNSCC. Here, we tested the effects of complement inhibition and its therapeutic potential in HNSCC. We conducted our studies using two Human Papilloma Virus (HPV)-negative HNSCC orthotopic mouse models. Complement C3aR and C5aR1 receptor antagonists were paired with radiation therapy (RT). Tumor growth was measured and immune populations from tumor, lymph node, and peripheral blood were compared among various treatment groups. Genetically engineered mouse models In contrast to established literature, inhibition of complement C3a and C5a signaling using receptor antagonists accelerated tumor growth in multiple HNSCC cell lines and corresponded with increased frequency of regulatory T cell (Treg) populations. Local C3a and C5a signaling has importance for CD4 T cell homeostasis and eventual development into effector phenotypes. Interruption of this signaling axis drives a phenotypic conversion of CD4 Our data establish Tregs as a pro-tumorigenic driver during complement inhibition and provide evidence that targeted C3a and C5a receptor inhibition may add therapeutic advantage when coupled with anti-Treg therapy.
Sections du résumé
BACKGROUND
Resistance to therapy is a major problem in treating head and neck squamous cell carcinomas (HNSCC). Complement system inhibition has been shown to reduce tumor growth, metastasis, and therapeutic resistance in other tumor models, but has yet to be explored in the context of HNSCC. Here, we tested the effects of complement inhibition and its therapeutic potential in HNSCC.
METHODS
We conducted our studies using two Human Papilloma Virus (HPV)-negative HNSCC orthotopic mouse models. Complement C3aR and C5aR1 receptor antagonists were paired with radiation therapy (RT). Tumor growth was measured and immune populations from tumor, lymph node, and peripheral blood were compared among various treatment groups. Genetically engineered mouse models
RESULTS
In contrast to established literature, inhibition of complement C3a and C5a signaling using receptor antagonists accelerated tumor growth in multiple HNSCC cell lines and corresponded with increased frequency of regulatory T cell (Treg) populations. Local C3a and C5a signaling has importance for CD4 T cell homeostasis and eventual development into effector phenotypes. Interruption of this signaling axis drives a phenotypic conversion of CD4
CONCLUSIONS
Our data establish Tregs as a pro-tumorigenic driver during complement inhibition and provide evidence that targeted C3a and C5a receptor inhibition may add therapeutic advantage when coupled with anti-Treg therapy.
Identifiants
pubmed: 33789881
pii: jitc-2021-002585
doi: 10.1136/jitc-2021-002585
pmc: PMC8016081
pii:
doi:
Substances chimiques
C3 protein, mouse
0
C5ar1 protein, mouse
0
Complement C3
0
Complement Inactivating Agents
0
Forkhead Transcription Factors
0
Foxp3 protein, mouse
0
Receptor, Anaphylatoxin C5a
0
Receptors, Complement
0
complement C3a receptor
0
Dexamethasone
7S5I7G3JQL
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 : NIDCR NIH HHS
ID : R01 DE028529
Pays : United States
Organisme : NIDCR NIH HHS
ID : R01 DE028282
Pays : United States
Organisme : NIDDK NIH HHS
ID : P30 DK116073
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: None declared.
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