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Nat Commun. 2019 Jun 11;10(1):2416. doi: 10.1038/s41467-019-10369-9.

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

Author information

1
Vall d Hebron Institute of Oncology (VHIO), Vall d'Hebron University Hospital, 08035, Barcelona, Spain.
2
CIBERONC, 028029, Madrid, Spain.
3
Vall d'Hebron Institut de Recerca (VHIR), Vall d'Hebron University Hospital, 08035, Barcelona, Spain.
4
Universitat Autònoma de Barcelona, 08193, Cerdanyola del Vallès, Spain.
5
Hospital Clinic, University of Barcelona and Institut d'Investigació Biomèdica August Pi i Sunyer (IDIBAPS), 08036, Barcelona, Spain.
6
Seve Ballesteros Foundation Brain Tumor Group, Spanish National Cancer Research Center, CNIO, 28029, Madrid, Spain.
7
Vall d Hebron Institute of Oncology (VHIO), Vall d'Hebron University Hospital, 08035, Barcelona, Spain. jseoane@vhio.net.
8
CIBERONC, 028029, Madrid, Spain. jseoane@vhio.net.
9
Universitat Autònoma de Barcelona, 08193, Cerdanyola del Vallès, Spain. jseoane@vhio.net.
10
Institució Catalana de Recerca i Estudis Avançats (ICREA), 08010, Barcelona, Spain. jseoane@vhio.net.

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.

PMID:
31186412
DOI:
10.1038/s41467-019-10369-9

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