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

• Published in: Nature communications 2019-06, Vol.10 (1), p.2416-2416, Article 2416
• Main Authors: Pascual-García, Mónica, Bonfill-Teixidor, Ester, Planas-Rigol, Ester, Rubio-Perez, Carlota, Iurlaro, Raffaella, Arias, Alexandra, Cuartas, Isabel, Sala-Hojman, Ada, Escudero, Laura, Martínez-Ricarte, Francisco, Huber-Ruano, Isabel, Nuciforo, Paolo, Pedrosa, Leire, Marques, Carolina, Braña, Irene, Garralda, Elena, Vieito, María, Squatrito, Massimo, Pineda, Estela, Graus, Francesc, Espejo, Carmen, Sahuquillo, Juan, Tabernero, Josep, Seoane, Joan
• Format: Article
• Language: English
• Subjects: 13; 13/106; 13/31; 13/51; 38; 38/39; 38/5; 631/67/327; 692/4028/67; Animals; Antibodies; Antibodies, Neutralizing - pharmacology; CD163 antigen; CD8 antigen; CD8-Positive T-Lymphocytes - immunology; CD8-Positive T-Lymphocytes - metabolism; Chemokine CCL2 - metabolism; Chemokine CXCL9 - metabolism; Epigenesis, Genetic; Humanities and Social Sciences; Humans; Immune checkpoint; Immunologic Memory; Immunological memory; Immunology; Immunotherapy; Infiltration; Leukemia Inhibitory Factor - antagonists & inhibitors; Leukemia Inhibitory Factor - immunology; Leukemia Inhibitory Factor - metabolism; Lymphocytes; Lymphocytes T; Lymphocytes, Tumor-Infiltrating - drug effects; Lymphocytes, Tumor-Infiltrating - immunology; Macrophages; Macrophages - immunology; Macrophages - metabolism; Metastases; Mice, Inbred C57BL; Mice, SCID; Monocyte chemoattractant protein 1; multidisciplinary; Neoplasm Transplantation; Neoplasms - drug therapy; Neoplasms - immunology; Neoplasms - pathology; PD-1 protein; Programmed Cell Death 1 Receptor - antagonists & inhibitors; Programmed Cell Death 1 Receptor - immunology; Science; Science (multidisciplinary); Tumor Microenvironment - immunology; Tumors
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-019-10369-9

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. LIF is a pleiotropic cytokine that promotes an immunosuppressive microenvironment and has critical functions in embryonic development. Here, the authors show that LIF regulates CD8 +  T cell tumor infiltration in cancer by repressing CXCL19 and promoting the presence of protumoral macrophages and thatLIF inhibition, via neutralizing antibodies, promotes T cell infiltration and synergizes with immune checkpoint inhbitors resulting in tumor regression and immunological memory.