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The impact of CXCL5 overexpression on the primary tumor microenvironment of B16F1 melanomas

ABSTRACT: CXCL5, a strong neutrophil-chemoattractant, has been reportet to be expressed in different cancer entities with diverse outcomes in disease progression. Contradictory outcome in disease progression in different tumor entities might be explained by a tumor type specific expression pattern of chemokines, chemokine receptors and growth factors that act in concert with CXCL5. This study evaluates the impact of CXCL5 expression on the tumor mircoenvironment in a syngeneic mouse melanoma model.

ORGANISM(S): Mus musculus

PROVIDER: GSE101104 | GEO | 2018/07/19

REPOSITORIES: GEO

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Project description:BACKGROUND: CXCR1/2 inhibitors are being implemented with immunotherapies in PDAC clinical trials. CXCL ligands are a family of cytokines responsible for stimulating these receptors; while typically secreted by activated immune cells, fibroblasts, and even adipocytes, they are also secreted by immune-evasive cancer cells. CXCL ligand release is known to occur in response to inflammatory stimuli, whether pathogenic (bacterial) or endogenous (obesity). Obesity has been linked to poor patient outcome and altered anti-tumor immunity in pancreatic cancer. Importantly, adipose-derived cytokines and chemokines have been implicated as potential drivers of tumor cell immune evasion; cumulatively these findings suggest that targeting CXC ligands may be beneficial in the context of obesity. METHODS: RNA-sequencing of human PDAC cell lines was used to assess differential influences of adipose conditioned media on the cancer cell transcriptome. In addition, the adipose-induced secretome of PDAC cells was validated with ELISA for induced CXCL5 secretion. Human tissue data from CPTAC was used to correlate IL-1β and TNF expression with both CXCL5 mRNA and protein levels. CRISPR-Cas9 was used to knock out CXCL5 from a murine PDAC cell line in order to assess orthotopic tumor studies in syngeneic, diet-induced obese mice. Flow cytometry was used to compare the immune profiles between tumors. Mice were monitored for differences in tumor size at endpoint in combination with Anti-PD-1 immune checkpoint blockade therapy. RESULTS: Human adipose conditioned media (hAT-CM) stimulates CXCL5 secretion from PDAC cells via either IL-1β or TNF; neutralization of both is required to significantly block release of CXCL5 from tumor cells. Ablation of CXCL5 from tumors promoted an enriched immune phenotype with an unanticipatedly increased number of exhausted CD8 T cells. Application of anti-PD-1 treatment to control tumors failed to alter tumor growth, yet treatment of CXCL5 deficient tumors showed response by significantly diminished tumor mass. CONCLUSIONS: In summary, our findings show that both TNF and IL-1β can stimulate CXCL5 release from PDAC cells in vitro, which correlates with expression in patient data. CXCL5 depletion in vivo alone is sufficient to promote T cell infiltration into tumors, increasing efficacy of checkpoint blockade inhibition and alleviating tumor burden.

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The impact of CXCL5 overexpression on the primary tumor microenvironment of B16F1 melanomas

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