Dichotomous effects of cellular expression of STAT3 on tumor growth of HNSCC.

TitleDichotomous effects of cellular expression of STAT3 on tumor growth of HNSCC.
Publication TypeJournal Article
Year of Publication2022
AuthorsBickett TE, Knitz MW, Piper M, Oweida AJ, Gadwa J, Darragh LB, Nguyen D, Bhatia S, Bhuvane S, Phan AV, Van Court B, Corbo S, Pham T, Dent AL, Lenz L, Karam SD
JournalMol Ther
Volume30
Issue3
Pagination1149-1162
Date Published2022 Mar 02
ISSN1525-0024
KeywordsAnimals, Head and Neck Neoplasms, Mice, Mice, Knockout, Squamous Cell Carcinoma of Head and Neck, STAT3 Transcription Factor, T-Lymphocytes, Regulatory, Tumor Microenvironment
Abstract

STAT3 signaling has been shown to regulate cellular function and cytokine production in the tumor microenvironment (TME). Within the head and neck squamous cell carcinoma (HNSCC) TME, we previously showed that therapeutic targeting of STAT3 in combination with radiation resulted in improved tumor growth delay. However, given the independent regulatory effects STAT3 has on anti-tumor immunity, we aimed to decipher the effects of individually targeting STAT3 in the cancer cell, regulatory T cells (Tregs), and natural killer (NK) cell compartments in driving tumor growth and resistance to therapy in HNSCCs. We utilized a CRISPR knockout system for genetic deletion of STAT3 within the cancer cell as well as two genetic knockout mouse models, FoxP3-Cre/STAT3 fl and NKp46-Cre/STAT3 fl, for Tregs and NK cell targeting, respectively. Our data revealed differences in development of resistance to treatment with STAT3 CRISPR knockout in the cancer cell, driven by differential recruitment of immune cells. Knockout of STAT3 in Tregs overcomes this resistance and results in Treg reprogramming and recruitment and activation of antigen-presenting cells. In contrast, knockout of STAT3 in the NK cell compartment results in NK cell inactivation and acceleration of tumor growth. These data underscore the complex interplay between the cancer cell and the immune TME and carry significant implications for drug targeting and design of combination approaches in HNSCCs.

DOI10.1016/j.ymthe.2021.11.011
Alternate JournalMol Ther
PubMed ID34793974
PubMed Central IDPMC8899526
Grant ListF32 DE030695 / DE / NIDCR NIH HHS / United States
P50 CA261605 / CA / NCI NIH HHS / United States
R01 DE028529 / DE / NIDCR NIH HHS / United States
T32 AI007405 / AI / NIAID NIH HHS / United States
T32 CA174648 / CA / NCI NIH HHS / United States
R01 DE028282 / DE / NIDCR NIH HHS / United States
R01 AI131662 / AI / NIAID NIH HHS / United States
Related Faculty: 
Andy Phan, M.D.

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