Receptor, TNFR2, Identified as Target for Immunotherapy

Receptor, TNFR2, Identified as Target for Immunotherapy

Some cancer therapies target cancer cells directly, while others are meant to boost the immune system to attack the malignant cells. Researchers at Massachusetts General Hospital might have found a way to do both, according to a new study.

Targeting the tumor necrosis factor receptor type 2 (TNFR2) directly destroys TNFR2-positive cancer cells and regulatory T cells (T-regs), thereby eliminating immunosuppresive signals. The study, “Targeting TNFR2 with antagonistic antibodies inhibits proliferation of ovarian cancer cells and tumor-associated Tregs,” published in Science Signaling, elaborates on that finding.

Antibody immunotherapy is showing great promise for combatting cancer. Several immune checkpoint inhibitors — including Keytruda (pembrolizumab), Opdivo (nivolumab), and Yervoy (ipilimumab) — dampen the tumor’s immunosuppressive signals and have been approved to treat different cancers. But because they inhibit molecules that are found in healthy T-cells, the drugs often have toxic effects, such as autoimmunity.

The MGH team found that blocking TNFR2 boosted the immune response — particularly within the tumor site — leaving other tissues unharmed, and that TNFR2 antibodies prevented T-regs from proliferating.

Because T-regs stop tumor-killing T-cells from doing their job, this effectively restored an anti-tumor immune response.

Blocking TNFR2 had a more potent effect on tumor-associated T-regs than on those from healthy individuals, suggesting TNFR2-positive cells are unique to the tumor microenvironment and that the method could reduce potential side effects caused by autoimmunity.

The team also found that the antagonistic TNFR2 antibodies could directly kill TNFR2-positive ovarian cancer cells in culture, suggesting that the receptor could be a target for cancer therapies.

“We have known for some time that TNFR2 is highly expressed in the tumor microenvironment, particular on the very important population of regulatory T cells, but we are now beginning to understand the potential efficacy of targeting cancer cells through the TNFR2 surface oncogene,” Denise Faustman, MD, PhD, corresponding author of the report and head of the Immunobiology Lab at MGH, said in a press release.

“(B)lockage of TNFR2 may have the effect of killing two birds with one stone: boosting anti-tumor immune responses and directly killing tumor cells,” Xin Chen, MD, PhD, of the National Cancer Institute and the University of Macau, and Joost J. Oppenheim, MD, of the National Cancer Institute wrote in an independent review article published in the same issue of Science Signaling.