Activation of CD3⁺ T cells by Helicobacter pylori DNA vaccines in potential immunotherapy of gastric carcinoma

Abstract

Most of gastric carcinoma (GC) is attributed to infection by Helicobacter pylori (H. pylori) but there is increasing evidence that the positive H. pylori status correlates with better prognosis in GC. The H. pyloriinduced cellular immune response may suppress cancer and in this work, recombinant pcDNA3 plasmids encoding various fragments of H. pylori virulence genes of cagA, vacA and babA are constructed and combined into groups to immunize BALB/c mice. The activated splenic CD3 + T cells are purified and the anticancer effects are investigated in vitro and in vivo. The H. pylori DNA vaccines induce a shift in the response from Th1 to Th2 that mimicks the immune status in patients of GC with chronic H. pylori infection. The stimulated CD3 + T cells inhibit the growth of human GC cells in vitro and adoptive transfusions of the CD3 + T cells suppress the growth of GC xenograft in vivo. The effects may be caused by the larger ratios of infiltrated CD8 + /CD4 + T cells, reduced infiltration of regulatory FOXP3 + T cells, and enhanced apoptosis induced by upregulation of Caspase-9/Caspase-3 and downregulation of Survivin. Our results reveal the potential immunotherapeutic value of H. pylori vaccine-activated CD3 + T cells in those with advanced GC.

Effect ofHelicobacter pylorion immunotherapy is gaining more attention

“…Recombinant DNA vaccines expressing H. pylori CagA, VacA, and blood‐group antigen‐binding adhesin gene (BabA) can activate CD3 + T cells in BALB/c mice model, and can inhibit the growth of human GC cells in vitro and the growth of GC xenograft in vivo. These results showed the potential immunotherapeutic value of H. pylori vaccine‐activated CD3 + T cells in advanced GC 33 . Second, the virulence factors of H. pylori can be used as immune adjuvant to recombine with oncolytic virus (OV), measles virus (MV) or other immunogens, and recombinant fusion proteins can synergistically exert anti‐tumor effect.…”

“…As we mentioned earlier, when H. pylori infected gastric epithelial cells, it will activate the NF‐kB pathway through CagA and HP‐NAP et al, resulting in a large release of cytokines and inflammatory factors in downstream of the pathway, causing gastric mucosal damage and inflammation 29 . Taking advantage of virulence factor as a good immune enhancer, many studies are now devoted to using H. pylori virulence factors as a cancer vaccine or immune adjuvant for cancer therapy 31–37 . At the same time, in order to avoid the host's immune response, H. pylori also upregulates the expression of PD‐1/PD‐L1 to inhibit the activity of T cells and other immune cells, thereby maintaining its own continuous colonization in the gastric mucosa 30,41 .…”

“…These results showed the potential immunotherapeutic value of H. pylori vaccine-activated CD3 + T cells in advanced GC. 33 Helicobacter pylori infection has a detrimental impact on the efficacy of cancer immunotherapies 16 Switzerland Mouse colon adenocarcinoma and melanoma, human non-smallcell lung cancer…”

“…29 Taking advantage of virulence factor as a good immune enhancer, many studies are now devoted to using H. pylori virulence factors as a cancer vaccine or immune adjuvant for cancer therapy. [31][32][33][34][35][36][37] At the same time, in order to avoid the host's immune response, H. pylori also upregulates the expression of PD-1/PD-L1 to inhibit the activity of T cells and other immune cells, thereby maintaining its own continuous colonization in the gastric mucosa. 30,41 Upregulation of PD-L1 expression and suppression of immune system hints that H. pylori may have adverse effects on immunotherapy.…”

Effects of helicobacter pylori on tumor microenvironment and immunotherapy responses

“…Moreover, H. pylori DNA vaccines encoding fragments of CagA, VacA, and BabA can induce Th1 shift to Th2 response in immunized BALB/c mice, which mimics the immune status of GC patients with chronic H. pylori infection. Stimulated CD3 + T cells inhibit the proliferation of human GC cells in vitro , and the adoptive infusion of CD3 + T cells inhibits the growth of GC xenografts in vivo ( 152 ).…”