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.
View: Text | PDF
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

×

Figure 1

Pulmonary melanoma metastasis stimulates PD-L1.

Options: View larger image (or click on image) Download as PowerPoint
Pulmonary melanoma metastasis stimulates PD-L1. Eight-week-old WT mice w...
Eight-week-old WT mice were challenged with B16-F10 (B16) melanoma cells or control vehicle (PBS) via tail vein injection and evaluated 2 weeks later. (A) Real-time reverse transcriptase (RT) PCR was used to quantitate the levels of mRNA encoding PD-L1 in the lungs from mice treated i.v. with PBS (B16 –) or B16 cells (B16 +). Each dot represents an evaluation in an individual animal. (B) Western blot evaluations of PD-L1 accumulation in lungs from mice treated with PBS (B16 –) or B16 cells (B16 +). (C and D) FACS evaluations quantitating the accumulation of PD-L1 in cell populations from lungs of mice treated with B16 cells (B16-F10 +) or vehicle control (B16-F10 –). These evaluations used specific markers of airway epithelial cells (CC10), alveolar epithelial cells (surfactant apoprotein C [SP-C]), T cells (CD3), and macrophages (CD68). (E) Representative double-label fluorescent immunohistochemical evaluations in lungs from mice challenged with B16 melanoma cells using cell-specific markers (alveolar epithelial cells, SP-C; macrophages, CD68) (red) and anti–PD-L1 (green). The arrows highlight cells that stained with both antibodies. The values in A represent the mean ± SEM of the noted evaluations represented by the individual dots. B–E are representative of a minimum of 2 similar evaluations. *P < 0.05, **P < 0.01, ***P < 0.001 (Student’s t test). Scale bars: 50 μm.