Abstract
Simple SummaryDespite the success of immune checkpoint inhibitors (ICI) for treating a variety of solid cancers, most gastric cancer patients are resistant to ICI monotherapies. Combinations of ICI with other therapies may be able to overcome this resistance. In order to develop combination immunotherapies, immunologically well-characterized preclinical gastric cancer models are required. To this end, in the present study, we characterized two murine gastric cancer cell lines, namely, YTN2 which spontaneously regresses, and YTN16 which grows progressively. Although anti-CTLA-4 monotherapy eradicated most YTN16 tumors, these were resistant to either anti-PD-1 or anti-PD-L1 treatment. Furthermore, we identified neoantigens in YTN2 and YTN16 tumors and conducted neoantigen-based immunotherapy for these tumors. In addition, the information on neoantigens facilitates the evaluation of tumor-specific immune responses induced by the combination therapies. These immunologically well-characterized gastric cancer models will contribute to the development of novel combination immunotherapies.To develop combination immunotherapies for gastric cancers, immunologically well-characterized preclinical models are crucial. Here, we leveraged two transplantable murine gastric cancer cell lines, YTN2 and YTN16, derived from the same parental line but differing in their susceptibility to immune rejection. We established their differential sensitivity to immune checkpoint inhibitors (ICI) and identified neoantigens. Although anti-CTLA-4 mAbs eradicated YTN16 tumors in 4 of 5 mice, anti-PD-1 and anti-PD-L1 mAbs failed to eradicate YTN16 tumors. Using whole-exome and RNA sequencing, we identified two and three neoantigens in YTN2 and YTN16, respectively. MHC class I ligandome analysis detected the expression of only one of these neoantigens, mutated Cdt1, but the exact length of MHC binding peptide was determined. Dendritic cell vaccine loaded with neoepitope peptides and adoptive transfer of neoantigen-specific CD8+ T cells successfully inhibited the YTN16 tumor growth. Targeting mutated Cdt1 had better efficacy for controlling the tumor. Therefore, mutated Cdt1 was the dominant neoantigen in these tumor cells. More mCdt1 peptides were bound to MHC class I and presented on YTN2 surface than YTN16. This might be one of the reasons why YTN2 was rejected while YTN16 grew in immune-competent mice.
Highlights
Gastric cancer is the fifth most frequent cancer and the fourth most common cause of cancer death worldwide [1]
We investigate the immunological characteristics of two gastric cancer cell sublines, YTN2 and YTN16, derived from the same parental line
We immunologically characterized two gastric cancer cell sublines derived from the same parental line but with very different behaviors
Summary
Gastric cancer is the fifth most frequent cancer and the fourth most common cause of cancer death worldwide [1]. Anti-PD-1 checkpoint blockade therapies, such as those employing treatment with the monoclonal antibodies pembrolizumab and nivolumab, have been trialed for treating advanced gastric cancer [2,3]. Pembrolizumab monotherapy has demonstrated anti-tumor activity in that small proportion of patients with metastatic gastric cancers having high microsatellite instability and Epstein–Barr virus-positivity [4], the majority of patients with more common forms of gastric cancer is resistant to such monotherapy. Many clinical trials are ongoing or have reached their endpoints, and recently, the combination of nivolumab plus chemotherapy has been approved by the FDA [5]. The antitumor effect is still not sufficient to cover all patients and the development of additional combination therapies remains an urgent need
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