Abstract
The role of the immune system in cancer progression has become increasingly evident over the past decade. Chronic inflammation in the promotion of tumorigenesis is well established, and cancer-associated tolerance/immune evasion has long been appreciated. Recent developments of immunotherapies targeting cancer-associated inflammation and immune tolerance, such as cancer vaccines, cell therapies, neutralizing antibodies, and immune checkpoint inhibitors, have shown promising clinical results. However, despite significant therapeutic advances, most patients diagnosed with metastatic cancer still succumb to their malignancy. Treatments are often toxic, and the financial burden of novel therapies is significant. Thus, new methods for utilizing similar biological systems to compare complex biological processes can give us new hypotheses for combating cancer. One such approach is comparing trophoblastic growth and regulation to tumor invasion and immune escape. Novel concepts regarding immune activation in pregnancy, especially reactivation of the immune system at labor through toll like receptor engagement by fetal derived DNA, may be applicable to cancer immunotherapy. This review summarizes mechanisms of inflammation in cancer, current immunotherapies used in the clinic, and suggestions for looking beyond oncology for novel methods to reverse cancer-associated tolerance and immunologic exhaustion utilizing mechanisms encountered in normal human pregnancy.
Highlights
Cancer is the complex orchestration of tumor and supporting stroma, immune mediators, and angiogenic factors that result in growth and metastasis of tumor cells, which lead to organ dysfunction and death if not successfully treated
Tumor cells are “self,” making it more challenging for natural killer (NK) cells, cytotoxic T lymphocytes (CTLs), and other cellular effectors involved in immunosurveillance to target tumor cells compared to cells infected with a virus
Patients with advanced melanoma exist in a state of systemic chronic inflammation, which is driven, in part, by high levels of vascular endothelial growth factor (VEGF)-A secreted by the tumor to suppress the cancer targeting activity of immune cells [4, 5]
Summary
Cancer is the complex orchestration of tumor and supporting stroma, immune mediators, and angiogenic factors that result in growth and metastasis of tumor cells, which lead to organ dysfunction and death if not successfully treated. Since immune cells become tolerized by the tumor, they might not respond to danger signals the way a healthy immune system would. This interesting immunologic paradox exists in the setting of pregnancy, where the mother is continually exposed to haploidentical “foreign” cells from the fetus but does not mount an immunologic attack that would be deleterious to the pregnancy. Patients with advanced melanoma exist in a state of systemic chronic inflammation, which is driven, in part, by high levels of vascular endothelial growth factor (VEGF)-A secreted by the tumor to suppress the cancer targeting activity of immune cells [4, 5]. The third barrier to successful immunotherapy is understanding when and how to couple immune-based therapies with standard cytotoxic chemotherapies or molecularly targeted treatments. We transition to immunologic mechanisms in pregnancy exploited by tumors, and conclude with emerging data regarding the potential benefit of cell-free (fetal) nucleic acids in the reconstitution and prolongation of anti-tumor immunity
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