Loss of cancer cell STAT1 improves response to radiation therapy and promotes T cell activation in head and neck squamous cell carcinoma
Resistance to radiation therapy (RT) remains an obstacle in HPV-negative head and neck squamous cell carcinomas (HNSCCs)—even with a combined RT-immunotherapy approach. Jak-Stat proteins have long been studied for both their immune regulatory role in the host immune response as well as their cancer...
Saved in:
Published in | Cancer Immunology, Immunotherapy Vol. 71; no. 5; pp. 1049 - 1061 |
---|---|
Main Authors | , , , , , , , , , , , |
Format | Journal Article |
Language | English |
Published |
Berlin/Heidelberg
Springer Berlin Heidelberg
01.05.2022
Springer Nature B.V |
Subjects | |
Online Access | Get full text |
Cover
Loading…
Summary: | Resistance to radiation therapy (RT) remains an obstacle in HPV-negative head and neck squamous cell carcinomas (HNSCCs)—even with a combined RT-immunotherapy approach. Jak-Stat proteins have long been studied for both their immune regulatory role in the host immune response as well as their cancer cell signaling role in shaping the tumor microenvironment (TME). Here, we identify STAT1 as a mediator of radioresistance in HPV-negative preclinical mouse models of HNSCC, by which knockout of STAT1 in the cancer cell (STAT1 KO)—but not in the host—resulted in decreased tumor growth alongside increased immune activation. We show that RT increases STAT1/pSTAT1 expression, which may act as a marker of radioresistance. Whereas RT increased JAK-STAT and interferon (IFN) signaling, transcriptomic analysis revealed that STAT1 KO in the cancer cell resulted in decreased expression of IFN-associated genes of resistance. In vitro experiments showed that STAT1 KO increased T cell chemoattraction and decreased baseline growth. These results indicate that STAT1 may serve a tumor-promoting role in the cancer cell and will inform biomarker development and treatment regimens for HNSCC incorporating RT. |
---|---|
Bibliography: | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 Authors’ contributions SDK and MWK designed the study and all experiments. MWK, TEB, SBu, and DN performed mouse studies. BVC performed irradiation. MWK, SBh, SC, DN, and AO performed in vitro experiments. AO performed cell proliferation assays and western blotting. MWK, LBD, and JG performed flow cytometry and analysis. MP and MWK performed scratch wound assays. Sbu and MWK performed boyden chamber assays and analysis. All authors advised throughout the course of the study. SDK and MWK wrote the manuscript. All authors discussed, revised, and approved the final manuscript. |
ISSN: | 0340-7004 1432-0851 1432-0851 |
DOI: | 10.1007/s00262-021-03059-3 |