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

Mónica Pascual-García ,Irene Braña ,Carlota Rubio-Pérez ,Ada Sala-Hojman ,Carolina Marques ,Josep Tabernero ,María Vieito ,Elena Garralda ,Carmen Espejo ,Alexandra Arias ,Isabel Huber-Ruano ,Juan Sahuquillo ,Isabel Cuartas ,Raffaella Iurlaro ,Laura Escudero ,Francesc Graus ,Ester Bonfill-Teixidor ,Leire Pedrosa ,Francisco Martínez‐Ricarte ,Ester Planas‐Rigol ,Estela Pineda ,Massimo Squatrito ,Paolo Nuciforo ,Joan Seoane

doi:10.1038/s41467-019-10369-9

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.

Highlights

Cancer response to immunotherapy depends on the infiltration of CD8+ T cells and the presence of tumor-associated macrophages within tumors
We observed a significant correlation between LIF and tumor-associated macrophages (TAMs) across several tumor types of The Cancer Genome Atlas (TCGA) (Fig. 1a, b, Supplementary Data 1)
Glioblastoma (GBM), prostate adenocarcinoma, thyroid cancer and ovarian cancer were the 4 tumor types exhibiting the highest correlations between LIF and TAMs, while showing a high LIF expression across tumor samples (Fig. 1a, b)

Summary

Introduction

Cancer response to immunotherapy depends on the infiltration of CD8+ T cells and the presence of tumor-associated macrophages within tumors. 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. LIF can act as an oncogenic factor through the induction of the self-renewal of cancer-initiating cells[8], the regulation of cancerassociated fibroblasts[9], as well as promoting radioresistance[10] and chemoresistance[11]. We find that tumors expressing high levels of LIF tend to be infiltrated with tumor-associated macrophages (TAMs). The combination of the blockade of LIF with checkpoint inhibitors induces tumor regression, immune memory, and an increase in overall survival

Methods

Results

Conclusion