Molecular and Immune Profiling of Syngeneic Mouse Models Predict Response to Immune Checkpoint Inhibitors in Gastric Cancer

• Published in: Cancer research and treatment Vol. 55; no. 1; pp. 167 - 178
• Main Authors: Lee, Dagyeong, Choi, Junyong, Oh, Hye Jeong, Ham, In-Hye, Lee, Sung Hak, Nomura, Sachiyo, Han, Sang-Uk, Hur, Hoon
• Format: Journal Article
• Language: English
• Published: Korea (South) Korean Cancer Association 01.01.2023; 대한암학회
• Subjects: Animals; Cell Line, Tumor; Cytokines; Immune Checkpoint Inhibitors - pharmacology; Immune Checkpoint Inhibitors - therapeutic use; Mice; Mice, Inbred C57BL; Original; Stomach Neoplasms - drug therapy; Stomach Neoplasms - genetics; T-Lymphocytes; 의학일반; Immune checkpoint inhibitors; Tumor immunity; Macrophages; Syngeneic mouse; Stomach neoplasms
• ISSN: 1598-2998; 2005-9256
• DOI: 10.4143/crt.2022.094

Appropriate preclinical mouse models are needed to evaluate the response to immunotherapeutic agents. Immunocompetent mouse models have rarely been reported for gastric cancer. Thus, we investigated immunophenotypes and responses to immune checkpoint inhibitor (ICI) in immunocompetent mouse models using various murine gastric cancer cell lines. We constructed subcutaneous syngeneic tumors with murine gastric cancer cell lines, YTN3 and YTN16, in C57BL/6J mice. Mice were intraperitoneally treated with IgG isotype control or an anti-programmed death-ligand 1 (PD-L1) neutralizing antibody. We used immunohistochemistry to evaluate the tumor-infiltrating immune cells of formalin-fixed paraffin-embedded mouse tumor tissues. We compared the protein and RNA expression between YTN3 and YTN16 cell lines using a mouse cytokine array and RNA sequencing. The mouse tumors revealed distinct histological and molecular characteristics. YTN16 cells showed upregulation of genes and proteins related to immunosuppression, such as Ccl2 (CCL2) and Csf1 (M-CSF). Macrophages and exhausted T cells were more enriched in YTN16 tumors than in YTN3 tumors. Several YTN3 tumors were completely regressed by the PD-L1 inhibitor, whereas YTN16 tumors were unaffected. Although treatment with a PD-L1 inhibitor increased infiltration of T cells in both the tumors, the proportion of exhausted immune cells did not decrease in the non-responder group. We confirmed the histological and molecular features of cancer cells with various responses to ICI. Our models can be used in preclinical research on ICI resistance mechanisms to enhance clinical efficacy.