Abstract A71: Chitinase-3-like-1: A new immunomodulatory target in lung cancer

Abstract

Abstract One of the most exciting breakthroughs in the cancer field is the discovery of immune checkpoint molecules (ICPs) such as PD-1 and its ligands PD-L1 and PD-L2 as an immune evasion mechanism for cancer cells. Although the immunotherapeutics targeting ICPs have great success in many tumors, including lung cancer, still the response rates are very limited. Thus, understanding the underlying regulatory mechanism for these molecules is essential to develop rational and new immunotherapeutic strategies to maximize the clinical outcomes for patients. Chitinase 3-like-1, as a proinflammatory and protumorigenic molecule, has increased expression in many solid tumors including lung cancer. Circulating levels of Chi3l1 are also highly correlated with poor prognosis and decreased survival rates. However, the specific role of Chi3l1 in tumor initiation and progression and as an immunomodulator in the pulmonary tumor microenvironment has not been adequately defined. Recently we have discovered that melanoma lung metastasis was significantly reduced in Chi3l1 null mutant (Brp39−/−) mice and the mice treated with anti-Chi3l1 antibody (FRG) while it was increased in overexpressing transgenic mice (YKL-40 Tg) compared to the controls, suggesting a critical role of Chi3l1 in metastatic spread and colonization. We also showed that Chi3l1 transgene expression leads to infiltration of immune cells, particularly myeloid cells into the lung, and causes dysregulated expression of PD-L1 on the macrophages. In vitro studies by using bone marrow-derived macrophages demonstrated a blunted IFNg induced PD-L1 expressions in Brp39−/− cells compared to WT controls. Additionally, we have found that the FRG antibody has synergizing effect on anti-PD1 treatment in metastatic lung cancer model. FRG antibody treatment can also effectively inhibit tumor development and also promotes CD8+ T-cell infiltration into the tumor area compared to control treatment in primary lung cancer model (K-ras+/G12D/ P53−/−mice). Overall, our studies demonstrated that Chi3l1 plays an important role in lung cancer development or progression through regulating PD-1/PD-L1/L2 axis and T-cell infiltration. These studies also highlight a significant therapeutic potential of FRG antibody for lung cancer as a single or combinational immunotherapeutic agent. Citation Format: Bedia Akosman, Bing Ma, Suchitra Kamle, Dilara Kurtulus, Chang-Min Lee, Chun Lee, Jack Elias. Chitinase-3-like-1: A new immunomodulatory target in lung cancer [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2019 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(3 Suppl):Abstract nr A71.