Inhibition of MNKs promotes macrophage immunosuppressive phenotype to limit CD8+ T cell antitumor immunity.

Autor:	Pham TN; Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA.; Jesse Brown VA Medical Center, Chicago, Illinois, USA., Spaulding C; Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA.; Jesse Brown VA Medical Center, Chicago, Illinois, USA., Shields MA; Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA.; The Robert H. Lurie Comprehensive Cancer Center, Chicago, Illinois, USA., Metropulos AE; Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA., Shah DN; Department of Surgery, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA., Khalafalla MG; Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA., Principe DR; Medical Scientist Training Program, College of Medicine, University of Illinois at Chicago, Chicago, Illinois, USA., Bentrem DJ; Jesse Brown VA Medical Center, Chicago, Illinois, USA.; The Robert H. Lurie Comprehensive Cancer Center, Chicago, Illinois, USA.; Department of Surgery, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA., Munshi HG; Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA.; Jesse Brown VA Medical Center, Chicago, Illinois, USA.; The Robert H. Lurie Comprehensive Cancer Center, Chicago, Illinois, USA.
Jazyk:	angličtina
Zdroj:	JCI insight [JCI Insight] 2022 May 09; Vol. 7 (9). Date of Electronic Publication: 2022 May 09.
DOI:	10.1172/jci.insight.152731
Abstrakt:	To elicit effective antitumor responses, CD8+ T cells need to infiltrate tumors and sustain their effector function within the immunosuppressive tumor microenvironment (TME). Here, we evaluate the role of MNK activity in regulating CD8+ T cell infiltration and antitumor activity in pancreatic and thyroid tumors. We first show that human pancreatic and thyroid tumors with increased MNK activity are associated with decreased infiltration by CD8+ T cells. We then show that, while MNK inhibitors increase CD8+ T cells in these tumors, they induce a T cell exhaustion phenotype in the tumor microenvironment. Mechanistically, we show that the exhaustion phenotype is not caused by upregulation of programmed cell death ligand 1 (PD-L1) but is caused by tumor-associated macrophages (TAMs) becoming more immunosuppressive following MNK inhibitor treatment. Reversal of CD8+ T cell exhaustion by an anti-PD-1 antibody or TAM depletion synergizes with MNK inhibitors to control tumor growth and prolong animal survival. Importantly, we show in ex vivo human pancreatic tumor slice cultures that MNK inhibitors increase the expression of markers associated with immunosuppressive TAMs. Together, these findings demonstrate a role of MNKs modulating a protumoral phenotype in macrophages and identify combination regimens involving MNK inhibitors to enhance antitumor immune responses.
Databáze:	MEDLINE
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