Immune Reactivation by Cell-Free Fetal DNA in Healthy Pregnancies Re-Purposed to Target Tumors: Novel Checkpoint Inhibition in Cancer Therapeutics

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.

Keywords: cell-free fetal DNA; circulating tumor DNA; immunotherapy; inflammation; toll like receptors.

Figure 1

Overview of how cell-free fetal derived RNA or DNA from pregnancy can activate an inflammatory immune response through toll like receptors, which could be applied to novel cancer treatments.

Figure 2

Activation of TLR signaling cascade on CD14+ monocytes with addition of cff-DNA. Venn diagrams showing similar genes involved in the TLR signaling pathway having a fold change cut off of 2. (A) Three different healthy CD14+ monocyte populations treated with the same cff-DNA. (B) One healthy CD14+ monocyte population treated with three different cff-DNAs.