Dr. Denise Faustman spoke with Cancer Network about TNFR2 and its emerging role in understanding regulatory T-cell behavior.
Denise L. Faustman, MD, PhD, is associate professor of medicine at Harvard University and director of the Immunobiology Laboratory at Massachusetts General Hospital in Boston. Research in her lab focuses on the immunobiology of cancer, transplantation, and autoimmune diseases. Cancer Network asked Dr. Faustman about her team’s work on tumor necrosis factor receptor 2 (TNFR2)’s emerging role in understanding regulatory T-cell behavior and antitumor immunity.
Cancer Network: What are tumor necrosis factor receptor 2 (TNFR2, or CD120b)’s normal functions or roles in regulatory T-cell (Treg) immunobiology?
Dr. Faustman: Although there are many proteins on Tregs, TNFR2 is a very high-density protein on Tregs, especially Tregs of the tumor microenvironment.
What really makes TNFR2 special is that it is the central signaling pathway for Treg expansion or Treg contraction. TNFR2 is the master control switch for expanding the Treg population. Myeloid-derived suppressor cells (MDSC), [in] the tumor microenvironment also express large amounts of surface TNFR2.
Cancer Network: TNFR2 is also overexpressed on some tumor surfaces. How does that affect T cell response to tumor tissue? Does it play a role in tumor immune evasion?
Dr. Faustman: TNFR2 is linked to a pro-growth pathway utilizing NFkB [nuclear factor kappa-B] signaling, one of the best understood pathways for cellular expansion. TNFR2 on the Tregs of the tumor microenvironments expands those cells; select tumors also express TNFR2 to also expand the tumor directly.
Cancer Network: You and others have proposed targeting TNFR2 to modulate antitumor immune response. How might that work?
Dr. Faustman: My lab and the lab or Dr. Joost Oppenheim have both worked on TNFR2 on Tregs for many years. We first realized that in autoimmunity too few Tregs had TNFR2 and more TNFR2 Tregs were needed. The Oppenheim lab, working on mouse cancers, realized TNFR2 was abundant on Tregs that were functionally very immune-suppressive and found in the tumor microenvironment. It was this 15-year journey that allowed this convergence of diverse data that supported the importance of TNFR2 Tregs in tightly-regulated immune responses.
Cancer Network: What advantages might target TNFR2 offer over existing immune checkpoint inhibition strategies with anti-PD-1/PD-L1 and anti-CTLA agents?
Dr. Faustman: For anti-PD1 and anti-CTLA4 -/- [homozygous negative] mice (and now humans treated with these drugs), autoimmunity is a frequent consequence, thus limiting many people from receiving these check point inhibitor drugs.
Anti-PD1 and anti-CTLA4 [therapy] likely leads to autoimmunity since these proteins are expressed on almost all Tregs so if you take down all Tregs with these drugs, autoimmunity will form.
What is beautiful about TNFR2-/- mice or treatment of mice with anti-TNFR2 drugs, is that no autoimmunity forms. TNFR2 Tregs in humans compose about 8-10% of all Tregs. It is only the restricted natural and select TNFR2 Tregs that are killed with TNFR2 antagonistic antibodies thus allowing the rest of the immune system to be much better controlled.
Cancer Network: Should TNFR2 inhibition be explored or investigated as part of combinatorial immunotherapy strategy, alongside existing immune checkpoint inhibitors?
Dr. Faustman: I think it depends on the cancer type. If a cancer is only dominated by TNFR2 Tregs but does not have the TNFR2 oncogene, then combo therapy trials will probably be tried first.
On the other hand, if a tumor has abundant tumor infiltrating TNFR2 Tregs and a tumor also vividly expressed TNFR2 as an oncogene then it might be feasible to have only an anti-TNFR2 therapy.