Gastrin Vaccine Alone and in Combination With an Immune Checkpoint Antibody Inhibits Growth and Metastases of Gastric Cancer

Abstract

Gastric cancer is a leading cause of cancer-related deaths worldwide. Recently, clinical studies have demonstrated that many of those with advanced gastric cancer are responsive to immune checkpoint antibody therapy, although the median survival even with these new agents is less than 12 months for advanced disease. The gastrointestinal peptide gastrin has been shown to stimulate growth of gastric cancer in a paracrine and autocrine fashion through the cholecystokinin-B receptor (CCK-BR), a receptor that is expressed in at least 56.6% of human gastric cancers. In the current investigation, we studied the role of the gastrin-CCK-BR pathway in vitro and in vivo as well as the expression of the CCK-BR in a human gastric cancer tissue array. CCK-BR and PD-L1 receptor expression and gastrin peptide was found in two murine gastric cancer cells (NCC-S1 and YTN-16) by qRT-PCR and immunocytochemistry. Treatment of NCC-S1 cells with gastrin resulted in increased growth. In vivo, the effects of a cancer vaccine that targets gastrin peptide (polyclonal antibody stimulator—PAS) alone or in combination with a Programed Death-1 antibody (PD-1 Ab) was evaluated in immune competent mice (N = 40) bearing YTN-16 gastric tumors. Mice were treated with PBS, PD-1 Ab (50 µg), PAS (250 µg), or the combination of PD-1 Ab with PAS. Tumor growth was significantly slower than controls in PAS-treated mice, and tumor growth was decreased even more in combination-treated mice. There were no metastases in any of the mice treated with PAS either alone or in combination with PD-1 Ab. Tumor proliferation by the Ki67 staining was significantly decreased in mice treated with PAS monotherapy or the combination therapy. PAS monotherapy or combined with PD-1 Ab increased tumor CD8+ T-lymphocytes and decreased the number of immunosuppressive M2-polarized tumor-associated macrophages. CCK-BR expression was identified in samples from a human tissue array by immunohistochemistry confirming the clinical relevance of this study. These results confirm the significance of the gastrin-CCK-BR signaling pathway in gastric cancer and suggest that the addition of a gastrin vaccine, PAS, to therapy with an immune checkpoint antibody may decrease growth and metastases of gastric cancer by altering the tumor microenvironment.

Role of tumor-associated macrophages in common digestive system malignant tumors

“…For instance, researchers created an injectable hydrogel that can shear-thin and is loaded with polyphyllin II and resiquimod, which can help potentiate localized immunotherapy of GC by repolarizing TAMs[ 78 ]. Polyclonal antibody stimulator monotherapy or combined with PD-1 antibody[ 79 ], as well as using a natural alkaloid product isolated from sophora alopecuroides. L, sophoridine[ 80 ], may decrease the number of immunosuppressive M2-polarized TAMs.…”

Tumour‐associated macrophages in gastric cancer: From function and mechanism to application

“…15 Additionally, Smith et al reported that gastrin vaccine alone or combined with PD-1 antibody restrained GC growth and metastasis by reducing the M2 TAMs in the TME. 153 Researchers used CD40-HER2 bispecific antibody to target CD40 and maintain the ubiquitination level of TRAF6/3, thereby increasing its degradation in macrophages and consequently activating the NF-κB pathway to increase M1 TAMs and offset trastuzumab resistance in HER2-positive GC cells. 16 Furthermore, Guo et al reported that dextran sulphate reduced the promoting effects of M2 TAMs on the angiogenesis, and migratory and invasive abilities of GC cells using co-culture assays.…”

Recent Progress and Future Perspectives of Immunotherapy in Advanced Gastric Cancer

“…Although cancer vaccine has shown favourable benefits in phase I and phase II trials against advanced gastric cancer, its clinical efficacy is low because of regulation and suppression from the host immune system. Novel strategies to overcome this limitation involve the development of combined therapies, for example, combination of cancer vaccine and immune modulator to avoid immune suppression, use of conventional chemotherapy in addition to cancer vaccine to enhance anti-tumour activity but reduce cytotoxicity (66).…”