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 2

CHI3L1 plays a critical role in B16 melanoma stimulation of pulmonary PD-L1.

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CHI3L1 plays a critical role in B16 melanoma stimulation of pulmonary PD...
Eight-week-old WT (Chi3l1+/+) and CHI3L1-null (Chi3l1–/–) mice were given B16 melanoma cells or vehicle control. They were also treated with an anti-CHI3L1 antibody (FRG) or isotype control antibodies, and PD-L1 expression was evaluated 2 weeks later. (A) RT-PCR was used to quantitate the levels of mRNA encoding PD-L1 in the lungs from mice treated i.v. with PBS vehicle (B16-F10 –) or B16 cells (B16-F10 +). WT and CHI3L1-null mice were used. Each dot represents an evaluation in an individual animal. (B) Western blot evaluations of PD-L1 accumulation in lungs from WT and CHI3L1-null mice treated with vehicle (B16-F10 –) or B16 cells (B16-F10 +). (C) RT-PCR was used to quantitate the levels of mRNA encoding PD-L1 in the lungs from mice treated i.v. with vehicle (B16-F10 –) or B16 cells (B16-F10 +). The mice were then treated with antibodies against CHI3L1 (FRG +) or isotype control antibodies (FRG –). Each dot represents an evaluation in an individual animal. (D) Western blot evaluations of PD-L1 accumulation in lungs from WT mice that were given control vehicle (B16-F10 –) or B16 cells (B16-F10 +) and treated with antibodies against anti-CHI3L1 (FRG +) or isotype control (FRG –) antibodies. (E) Double-label immunohistochemical comparison of lungs from WT and Chi3l1–/– mice challenged with B16 melanoma cells using a macrophage-specific marker (CD68; green) and anti–PD-L1 antibodies (red). The plotted values in A and C represent the mean ± SEM of the noted evaluations represented by the individual dots. B, D, and E are representative of a minimum of 2 similar evaluations. **P < 0.01, ***P < 0.001 (Student’s t test). Scale bars: 100 μm.