IL-27 overexpression interferes with tumor regression mediated by anti-PD1 administration
Nataliya Shifrin, Melissa Koshlaychuk, Rene de Waal Malefyt
Merck Research Labs, Palo Alto, CA
IL-27 is a heterodimeric cytokine composed of two subunits: p28 and Epstein-Barr virus induced gene 3 (EBI3). It is produced by dendritic cells and macrophages in response to activation via Toll-like receptor signaling or pro-inflammatory cytokine stimulation. IL-27 receptor is abundantly expressed on activated T cells and NK cells. IL-27 receptor signaling on CD4 T cells promotes Th1 differentiation and inhibits differentiation into Th2 and Th17 subsets. Thus IL-27 appears to have both pro- and anti-inflammatory properties.
To investigate the role of IL-27 over-expression on anti-tumor immune responses we generated mice carrying a tamoxifen-inducible IL-27 transgene and challenged them with the syngeneic colon cancer cell line MC38. Upon establishment of the tumor, mice were administered tamoxifen to induce IL-27 expression by itself and/or treated with anti-PD1 mAbs.
IL-27 overexpression on its own had no effect on the rate of tumor growth and did not result in any significant changes in gene expression within the tumors. As expected, treatment with anti-PD1 lead to a significant reduction is tumor size or complete tumor regression which was accompanied by changes in expression of immune related genes in the tumor. Surprisingly, combining IL-27 over-expression with anti-PD1 treatment led to increased tumor size compared to anti-PD1 treatment alone and a significantly smaller proportion of animals with complete tumor regression.
Analysis of gene expression within the tumors points to an inhibition of the anti-PD1 mediated anti-tumor response by a potential defect in T cell infiltration, proliferation, and/or survival in tumors of IL-27 overexpressing animals.
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