Abstract
Immunotherapy is becoming a popular treatment modality in combat against cancer, one of the world’s leading health problems. While tumor cells influence host immunity via expressing immune inhibitory signaling proteins, some bacteria possess immunomodulatory activities that counter the symptoms of tumors. The accumulation of Salmonella in tumor sites influences tumor protein expression, resulting in T cell infiltration. However, the molecular mechanism by which Salmonella activates T cells remains elusive. Many tumors have been reported to have high expressions of programmed death-ligand 1 (PD-L1), which is an important immune checkpoint molecule involved in tumor immune escape. In this study, Salmonella reduced the expression of PD-L1 in tumor cells. The expression levels of phospho-protein kinase B (P-AKT), phospho-mammalian targets of rapamycin (P-mTOR), and the phospho-p70 ribosomal s6 kinase (P-p70s6K) pathway were revealed to be involved in the Salmonella-mediated downregulation of PD-L1. In a tumor-T cell coculture system, Salmonella increased T cell number and reduced T cell apoptosis. Systemic administration of Salmonella reduced the expressions of PD-L-1 in tumor-bearing mice. In addition, tumor growth was significantly inhibited along with an enhanced T cell infiltration following Salmonella treatment. These findings suggest that Salmonella acts upon the immune checkpoint, primarily PD-L1, to incapacitate protumor effects and thereby inhibit tumor growth.
Highlights
Conventional therapies, such as surgery, radiation therapy, and chemotherapy, have been used to destroy tumor cells directly, and immunotherapy has provided another option for patients who are suffering from the inefficiency of conventional treatments, primarily due to the emergence of high-grade malignant phenotypes and tumor cell drug resistance
The protein levels of programmed death-ligand 1 (PD-L1) were measured in murine cancer cell lines and human non-small cell lung cancer cell lines (NSCLC)
We suggested that the AKT/mammalian targets of rapamycin (mTOR) axis might be involved in the effect of Salmonella on PD-L1 expression
Summary
Conventional therapies, such as surgery, radiation therapy, and chemotherapy, have been used to destroy tumor cells directly, and immunotherapy has provided another option for patients who are suffering from the inefficiency of conventional treatments, primarily due to the emergence of high-grade malignant phenotypes and tumor cell drug resistance. In using immunotherapy for cancer treatment, the co-stimulatory and co-inhibitory immune checkpoints play an important role in naïve. Cluster of differentiation 28 (CD28) was the first molecule recognized as a co-stimulatory checkpoint. The engagement of T cell receptor (TCR) with CD28 induces naïve T cell proliferation and differentiation. The co-inhibitory molecules, such as cytotoxic T lymphocyte antigen 4. Cancers 2020, 12, 57 others regulate T cell cytokine secretion (e.g., interferon-γ, IFN-γ), proliferation and apoptosis [1]. PD-L1—one of the ligands of PD-1—was thought to inactivate T cell proliferation, cytokine production, and cytotoxicity. Patients who failed to respond to anti-PD-1 antibodies showed higher circulating exosomal PD-L1 expression [2]
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