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

Mónica Pascual-García, Ester Bonfill-Teixidor, Ester Planas-Rigol, Carlota Rubio-Perez, Raffaella Iurlaro, Alexandra Arias, Isabel Cuartas, Ada Sala-Hojman, Laura Escudero, Francisco Martínez-Ricarte, Isabel Huber-Ruano, Paolo Nuciforo, Leire Pedrosa, Carolina Marques, Irene Braña, Elena Garralda, María Vieito, Massimo Squatrito, Estela Pineda, Francesc Graus, Carmen Espejo, Juan Sahuquillo, Josep Tabernero and Joan Seoane ()
Additional contact information
Mónica Pascual-García: Vall d’Hebron University Hospital
Ester Bonfill-Teixidor: Vall d’Hebron University Hospital
Ester Planas-Rigol: Vall d’Hebron University Hospital
Carlota Rubio-Perez: Vall d’Hebron University Hospital
Raffaella Iurlaro: Vall d’Hebron University Hospital
Alexandra Arias: Vall d’Hebron University Hospital
Isabel Cuartas: Vall d’Hebron University Hospital
Ada Sala-Hojman: Vall d’Hebron University Hospital
Laura Escudero: Vall d’Hebron University Hospital
Francisco Martínez-Ricarte: Vall d’Hebron University Hospital
Isabel Huber-Ruano: Vall d’Hebron University Hospital
Paolo Nuciforo: Vall d’Hebron University Hospital
Leire Pedrosa: University of Barcelona and Institut d’Investigació Biomèdica August Pi i Sunyer (IDIBAPS)
Carolina Marques: Spanish National Cancer Research Center, CNIO
Irene Braña: Vall d’Hebron University Hospital
Elena Garralda: Vall d’Hebron University Hospital
María Vieito: Vall d’Hebron University Hospital
Massimo Squatrito: Spanish National Cancer Research Center, CNIO
Estela Pineda: University of Barcelona and Institut d’Investigació Biomèdica August Pi i Sunyer (IDIBAPS)
Francesc Graus: University of Barcelona and Institut d’Investigació Biomèdica August Pi i Sunyer (IDIBAPS)
Carmen Espejo: Vall d’Hebron University Hospital
Juan Sahuquillo: Vall d’Hebron University Hospital
Josep Tabernero: Vall d’Hebron University Hospital
Joan Seoane: Vall d’Hebron University Hospital

Nature Communications, 2019, vol. 10, issue 1, 1-11

Abstract: 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.

Date: 2019
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DOI: 10.1038/s41467-019-10369-9

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