G-CSF Is a Novel Mediator of T-Cell Suppression and an Immunotherapeutic Target for Women with Colon Cancer

Autor: Anita L. Ray, Apryl S. Saunders, Robert A. Nofchissey, Megan A. Reidy, Maria Kamal, Megan R. Lerner, Kar-Ming Fung, Mark L. Lang, Joshua A. Hanson, Shaoxuan Guo, Maria G. Urdaneta-Perez, Samara E. Lewis, Michael Cloyde, Katherine T. Morris
Rok vydání: 2023
Předmět:
Zdroj: Clinical Cancer Research. 29:2158-2169
ISSN: 1557-3265
1078-0432
Popis: Purpose: G-CSF enhances colon cancer development. This study defines the prevalence and effects of increased G-CSF signaling in human colon cancers and investigates G-CSF inhibition as an immunotherapeutic strategy against metastatic colon cancer. Experimental Design: Patient samples were used to evaluate G-CSF and G-CSF receptor (G-CSFR) levels by IHC with sera used to measure G-CSF levels. Peripheral blood mononuclear cells were used to assess the rate of G-CSFR+ T cells and IFNγ responses to chronic ex vivo G-CSF. An immunocompetent mouse model of peritoneal metastasis (MC38 cells in C57Bl/6J) was used to determine the effects of G-CSF inhibition (αG-CSF) on survival and the tumor microenvironment (TME) with flow and mass cytometry. Results: In human colon cancer samples, the levels of G-CSF and G-CSFR are higher compared to normal colon tissues from the same patient. High patient serum G-CSF is associated with increases in markers of poor prognosis, (e.g., VEGF, IL6). Circulating T cells from patients express G-CSFR at double the rate of T cells from controls. Prolonged G-CSF exposure decreases T cell IFNγ production. Treatment with αG-CSF shifts both the adaptive and innate compartments of the TME and increases survival (HR, 0.46; P = 0.0237) and tumor T-cell infiltration, activity, and IFNγ response with greater effects in female mice. There is a negative correlation between serum G-CSF levels and tumor-infiltrating T cells in patient samples from women. Conclusions: These findings support G-CSF as an immunotherapeutic target against colon cancer with greater potential benefit in women.
Databáze: OpenAIRE