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 9

Bispecific antibodies that simultaneously target CHI3L1 and PD-1 induce synergistic CTL-mediated tumor cell death responses and tumor cell PTEN expression.

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Bispecific antibodies that simultaneously target CHI3L1 and PD-1 induce ...
The antitumor effects of the FRGxPD-1 bispecific antibody were evaluated in a coculture system containing TALL-104 cells and A375 human melanoma cells. TALL-104 cells were activated by pretreatment with anti-CD3 and anti-CD28 (1 μg/mL each; incubation for 2 hours in 5% CO2 and air at 37°C). The TALL-104 cells were then cocultured with A357 human melanoma cells for 24 hours. These cocultures were undertaken in the presence of the following antibodies: isotype control antibody (5 μg/mL), anti–PD-1 or anti-CHI3L1 (FRG) alone (5 μg/mL) or in combination (2.5 μg/mL each), and the bispecific FRGxPD-1 antibody (5 μg/mL). (Row A) Representative demonstration of apoptotic tumor cell death using the In Situ Cell Death Detection Kit with fluorescein-dUTP. TUNEL+ cells are stained green. (Rows B–D) Representative demonstration of TALL-104 T cell expression of CD8 (B), perforin (C), and granzyme (D). Tumor cells are green, and positive-staining TALL-104 cells are yellow-orange. (Row E) Representative demonstration of tumor cell PTEN. Tumor cells are green, and PTEN is yellow-orange. (F) Quantification of the evaluations in A–E. The percentage of TUNEL+ tumor cells (row A), percentage of TALL-104 cells expressing CD8 (row B), perforin (row C), and granzyme (row D) adherent to tumor cells, and percentage of tumor cells expressing PTEN (row E) are illustrated. These evaluations were done using fluorescent microscopy (original magnification, ×20). In these quantifications, 5 randomly selected fields were evaluated. The values in F are the mean ± SEM of the noted 5 evaluations. **P < 0.01, ***P < 0.001 (1-way ANOVA with Tukey’s post hoc test). Scale bar: 10 μm (applies to all subpanels of A–E).