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CCL5 production in lung cancer cells leads to an altered immune microenvironment and promotes tumor development.

Authors :
Melese, Etienne S.
Franks, Elizabeth
Cederberg, Rachel A.
Harbourne, Bryant T.
Shi, Rocky
Wadsworth, Brennan J.
Collier, Jenna L.
Halvorsen, Elizabeth C.
Johnson, Fraser
Luu, Jennifer
Min Hee Oh
Vivian Lam
Krystal, Gerald
Hoover, Shelley B.
Raffeld, Mark
Simpson, R. Mark
Unni, Arun M.
Lam, Wan L.
Lam, Stephen
Abraham, Ninan
Source :
OncoImmunology; 2022, Vol. 11 Issue 1, p1-12, 12p
Publication Year :
2022

Abstract

Current immunotherapies for lung cancer are only effective in a subset of patients. Identifying tumorderived factors that facilitate immunosuppression offers the opportunity to develop novel strategies to supplement and improve current therapeutics. We sought to determine whether expression of driver oncogenes in lung cancer cells affects cytokine secretion, alters the local immune environment, and influences lung tumor progression. We demonstrate that oncogenic EGFR and KRAS mutations, which are early events in lung tumourigenesis, can drive cytokine and chemokine production by cancer cells. One of the most prominent changes was in CCL5, which was rapidly induced by KRAS<superscript>G12V</superscript> or EGFR<superscript>L858R</superscript> expression, through MAPK activation. Immunocompetent mice implanted with syngeneic KRAS-mutant lung cancer cells deficient in CCL5 have decreased regulatory T cells (T<subscript>regs</subscript>), evidence of T cell exhaustion, and reduced lung tumor burden, indicating tumor-cell CCL5 production contributes to an immune suppressive environment in the lungs. Furthermore, high CCL5 expression correlates with poor prognosis, immunosuppressive regulatory T cells, and alteration to CD8 effector function in lung adenocarcinoma patients. Our data support targeting CCL5 or CCL5 receptors on immune suppressive cells to prevent formation of an immune suppressive tumor microenvironment that promotes lung cancer progression and immunotherapy insensitivity. [ABSTRACT FROM AUTHOR]

Details

Language :
English
ISSN :
21624011
Volume :
11
Issue :
1
Database :
Complementary Index
Journal :
OncoImmunology
Publication Type :
Academic Journal
Accession number :
161372683
Full Text :
https://doi.org/10.1080/2162402X.2021.2010905