November 18, 2021 @ 4:00 pm - 5:00 pm
Free- This event has passed.
Monthly talks spotlight researchers engaged in discovering and validating therapeutic targets, biomarkers, developing novel agents and conducting clinical research.
“Cancer-associated Fibroblasts”
Sandra Orsulic, Ph.D.
Professor in Residence, Obstetrics and Gynecology
UCLA David Geffen School of Medicine
Thursday, Nov. 18, 2021
4-5 p.m.
Cancer-associated fibroblasts (CAFs) can induce therapeutic resistance by blocking access of chemotherapies and immunotherapies and physically hindering the trafficking of functional immune cells to the tumor parenchyma. CAF-secreted transforming growth factor beta (TGFβ) is a potent cytokine that promotes pro-tumorigenic CAF and immune cell phenotypes.
Studies have shown that therapeutic efficacy can be drastically improved by co-administration of TGFβ-blocking agents. However, targeting TGFβ has been associated with toxicity, possibly because TGFβ is a pleiotropic cytokine expressed by multiple stromal cell types, some of which are required for normal tissue homeostasis. Less attention has been paid to another member of the TGFβ superfamily, Activin-A (encoded by the INHBA gene).
We showed that INHBA expression was restricted to CAFs and the normal placenta while other normal tissues did not express INHBA. Functional knockdown assays demonstrated that INHBA is important for the contraction, proliferation, and invasion of human ovarian CAFs in vitro.
In a syngeneic mouse model of ovarian cancer, suppression of INHBA expression in the host fibroblasts reduced tumor growth. Multiplex immunoassays demonstrated that metastatic tumors enriched for INHBA-positive CAFs were also enriched for regulatory T-cells (Tregs).
Co-culture experiments with human ovarian CAFs and naive T cells showed that Treg differentiation was dependent on direct contact with INHBA-expressing CAFs. Mechanistically, INHBA/recombinant Activin-A in CAFs induced autocrine expression of PD-L1 through SMAD2-dependent signaling, which promoted Treg differentiation. Considering the overlapping functions of Activin-A and TGFβ, targeting Activin-A may be an effective method to inhibit tumor progression without significant toxicity to normal tissues.
Sandra Orsulic, Ph.D.
Professor in Residence, Obstetrics and Gynecology
UCLA David Geffen School of Medicine
Thursday, Nov. 18, 2021
4-5 p.m.