Back to Search Start Over

CHI3L1 regulates PD-L1 and anti-CHI3L1-PD-1 antibody elicits synergistic antitumor responses.

CHI3L1 regulates PD-L1 and anti-CHI3L1-PD-1 antibody elicits synergistic antitumor responses.

Authors :
Ma B
Akosman B
Kamle S
Lee CM
He CH
Koo JS
Lee CG
Elias JA
Source :
The Journal of clinical investigation [J Clin Invest] 2021 Nov 01; Vol. 131 (21).
Publication Year :
2021

Abstract

Evasion of the immune response is a hallmark of cancer, and programmed cell death 1 (PD-1) and PD-1 ligand 1 (PD-L1) are major mediators of this immunosuppression. Chitinase 3-like 1 (CHI3L1) is induced in many cancers, where it portends a poor prognosis and contributes to tumor metastasis and spread. However, the mechanism(s) that CHI3L1 uses in metastasis have not been defined. Here we demonstrate that CHI3L1 regulates the expression of PD-L1, PD-L2, PD-1, LAG3, and TIM3 and plays a critical role in melanoma progression and lymphatic spread. CHI3L1 also contributed to IFN-γ-stimulated macrophage PD-L1 expression, and RIG-like helicase innate immunity suppressed CHI3L1, PD-L1, and melanoma progression. Individual antibodies against CHI3L1 or PD-1 had discrete antitumor effects and additive antitumor responses in metastasis models and T cell-tumor cell cocultures when administered simultaneously. Synergistic cytotoxic tumor cell death was seen in T cell-tumor cell cocultures, and significantly enhanced antitumor responses were seen in in vivo tumor models treated with bispecific antibodies that simultaneously target CHI3L1 and PD-1. CHI3L1 contributes to tumor progression by stimulating the PD-1/PD-L1 axis and other checkpoint molecules. The simultaneous targeting of CHI3L1 and the PD-1/PD-L1 axis with individual and, more powerfully, with bispecific antibodies represents a promising therapy for pulmonary metastasis and progression.

Details

Language :
English
ISSN :
1558-8238
Volume :
131
Issue :
21
Database :
MEDLINE
Journal :
The Journal of clinical investigation
Publication Type :
Academic Journal
Accession number :
34720089
Full Text :
https://doi.org/10.1172/JCI137750