CHI3L1 regulates PD-L1 and anti–CHI3L1–PD-1 antibody elicits synergistic antitumor responses
Bing Ma, … , Chun Geun Lee, Jack A. Elias
Bing Ma, … , Chun Geun Lee, Jack A. Elias
Published November 1, 2021
Citation Information: J Clin Invest. 2021;131(21):e137750. https://doi.org/10.1172/JCI137750.
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Research Article Immunology Oncology

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

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.

Authors

Bing Ma, Bedia Akosman, Suchitra Kamle, Chang-Min Lee, Chuan Hua He, Ja Seok Koo, Chun Geun Lee, Jack A. Elias

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Figure 6

IFN-γ stimulates macrophage PD-L1 via a CHI3L1-dependent mechanism.

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IFN-γ stimulates macrophage PD-L1 via a CHI3L1-dependent mechanism. Bone...
Bone marrow–derived macrophages (BMDMs) prepared from 6- to 8-week-old WT, Chi3l1–/–, IL-13Ra2–/–, Tmem219–/–, and galectin-3–null (Gal3–/–) mice were used to evaluate the importance of CHI3L1 in recombinant IFN-γ (rIFN-γ) stimulation of PD-L1. (A and B) Dose and time dependency of IFN-γ stimulation of PD-L1 mRNA in BMDMs. BMDMs from WT mice were incubated with the noted concentrations of rIFN-γ for the noted periods of time. (C) RT-PCR evaluation of the expression of CHI3L1 in BMDMs after stimulation with rIFN-γ for 24 hours. (D) Western blot evaluations of the dose and time dependency of IFN-γ stimulation of macrophage CHI3L1 accumulation. (E) Western blot evaluations of rIFN-γ–stimulated PD-L1 accumulation in BMDMs prepared from WT and Chi3l1–/– mice. (F) FACS evaluations of the ability of IFN-γ to stimulate PD-L1 in BMDMs prepared from WT and Chi3l1–/– mice. (G) FACS evaluations of the ability of IFN-γ to stimulate PD-L1 accumulation in BMDMs prepared from WT, IL-13Ra2–/–, Tmem219–/–, and Gal3–/– mice and WT BMDMs treated with vehicle (5% DMSO) or the selective CRTH2 inhibitor (CAY10471, 20 μg/mL in 5% DMSO). The values in A–C represent the mean ± SEM of the evaluations represented by the individual dots. D–G are representative of a minimum of 2 similar evaluations. **P < 0.01, ***P < 0.001 (1-way ANOVA with Tukey’s post hoc test).