LIF regulates CXCL9 in tumor-associated macrophages and prevents CD8+ T cell tumor-infiltration impairing anti-PD1 therapy

Pascual García, Mónica; Bonfill Teixidor, Ester; Planas Rigol, Ester; Rubio-Perez, Carlota; Iurlaro, Raffaella; Arias Piñeiro, Alexandra; Cuartas Maza, Ma Isabel; Sala Hojman, Ada; Escudero Monreal, Laura; Martínez Ricarte, Francisco Ramón; Huber Ruano, Isabel; Nuciforo, Paolo Giovanni; Braña Garcia, Irene; Garralda Cabanas, Elena; Vieito Villar, Maria; Espejo Ruiz, Carmen; Sahuquillo Barris, Joan; Tabernero Caturla, Josep; Seoane Suarez, Joan

Abstract

Cancer response to immunotherapy depends on the infiltration of CD8+ T cells and the presence of tumor-associated macrophages within tumors. Still, little is known about the determinants of these factors. We show that LIF assumes a crucial role in the regulation of CD8+ T cell tumor infiltration, while promoting the presence of protumoral tumor-associated macrophages. We observe that the blockade of LIF in tumors expressing high levels of LIF decreases CD206, CD163 and CCL2 and induces CXCL9 expression in tumor-associated macrophages. The blockade of LIF releases the epigenetic silencing of CXCL9 triggering CD8+ T cell tumor infiltration. The combination of LIF neutralizing antibodies with the inhibition of the PD1 immune checkpoint promotes tumor regression, immunological memory and an increase in overall survival.

Keywords

Cancer; Tumor-associated macrophages; CD8

Bibliographic citation

Pascual-García M, Bonfill-Teixidor E, Planas-Rigol E, Rubio-Perez C, Iurlaro R, Arias A, et al. LIF regulates CXCL9 in tumor-associated macrophages and prevents CD8+ T cell tumor-infiltration impairing anti-PD1 therapy. Nat Commun. 2019;10(1):2416.