J Pathol Transl Med.  2020 Jan;54(1):20-33. 10.4132/jptm.2019.10.08.

Tumor immune response and immunotherapy in gastric cancer

• Kwak Y
• Seo AN
• Lee HE
• Lee HS

• KMID: 2501592
• DOI: http://doi.org/10.4132/jptm.2019.10.08

Abstract

Remarkable developments in immuno-oncology have changed the landscape of gastric cancer (GC) treatment. Because immunotherapy intervenes with tumor immune response rather than directly targeting tumor cells, it is important to develop a greater understanding of tumor immunity. This review paper summarizes the tumor immune reaction and immune escape mechanisms while focusing on the role of T cells and their co-inhibitory signals, such as the immune checkpoint molecules programmed death-1 and programmed deathligand 1 (PD-L1). This paper also describes past clinical trials of immunotherapy for patients with GC and details their clinical implications. Strong predictive markers are essential to improve response to immunotherapy. Microsatellite instability, Epstein-Barr virus, PD-L1 expression, and tumor mutational burden are now regarded as potent predictive markers for immunotherapy in patients with GC. Novel immunotherapy and combination therapy targeting new immune checkpoint molecules such as lymphocyte-activation gene 3, T cell immunoglobulin, and mucin domain containing-3, and indoleamine 2,3-dioxygenase have been suggested, and trials are ongoing to evaluate their safety and efficacy. Immunotherapy is an important treatment option for patients with GC and has great potential for improving patient outcome, and further research in immuno-oncology should be carried out.

Keyword

Stomach neoplasms; Immunotherapy; Programmed cell death-ligand 1; Microsatellite instability; Epstein-Barr virus; Tumor mutational burden; Tumor-infiltrating lymphocytes; Biomarker

Figure

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  Fig. 1. Cell-mediated tumor immunity. (A) Altered proteins are produced following genetic mutation of tumor cells or viral genes in tumor cells. Neoantigens can arise from these altered tumor proteins and be presented on tumor cell surface via major histocompatibility complex. Newly formed antigens on tumor cell surfaces are recognized by the immune system, and the tumor immune reaction is initiated. (B) T cell responses are generated by two signals. The first signal is binding between neoantigen presented on major histocompatibility complex (MHC) molecule and T cell receptor (TCR). The second signal is co-inhibitory or co-stimulatory and determines whether T cells will be activated or not. Programmed cell death protein-1 (PD-1), lymphocyte-activation gene 3, and T cell immunoglobulin, and mucin domain containing-3 are well known co-inhibitory receptors that bind specific ligands, such as programmed death-ligand 1 (PD-L1) or PD-L2. Binding between co-inhibitory receptors and their ligands induces T cell inactivation. Blockade of these co-inhibitory signals is the basic strategy for cancer immunotherapy.

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  Fig. 2. Representative figure of PD-L1 22C3 PharmDx assay. Most tumor cells show membranous staining. Some immune cells adjacent to tumor cells also had immunoreactivity to programmed death-ligand 1.

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  Fig. 3. Representative figure of Epstein-Barr virus (EBV) in situ hybridization. This case was diagnosed as gastric carcinoma with lymphoid stroma. EBV-positive cells highlight tumor cell clusters that form vague glandular structures.

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