Summary authored by Amir Ameri, MD

Bedside to Bench: Investigating Response & Resistance Mechanisms to Immune Checkpoint Therapy

Amir Ameri, MD

Dr. Sharma delivered an outstanding presentation, “Perspectives on Bench to Bedside Research.”Dr. Sharma discussed novel immunotherapeutic strategies for the treatment of metastatic solid tumors and highlighted the important roles a variety of immune cells and signaling pathways play in immune checkpoint blockade therapies. For example, the ICOS/ICOSL pathway is necessary for effective anti-tumor immune responses in the setting of anti-CTLA4 blockade. ICOS (inducible costimulatory) belongs to the CD28/CTLA4 family, and its expression is increased on activated T cells, including regulatory T cells. ICOS is also associated with follicular helper cells that help B cells mature. Targeting ICOS plus anti-CTLA4 togetherimproves anti-tumor immune responses because ICOS induces signaling via PI3K to promote Tbet expression with subsequent Th1 responses and tumor rejection.

Dr. Sharma also discussed the role of tertiary lymphoid structures as markers of response to immune checkpoint blockade.  Dr. Sharma highlighted how anti-tumor immune responses depend on the context in which they occur. For example, she investigated why clinical responses to immunotherapy occur less frequently in bone metastases and found low Th1 and high Th17 signature in the bone microenvironment. Given that IL-6 and TGF-beta drive Th17 differentiation, she tried inhibiting the TGF-beta pathway. The combination of anti-TGF-beta with anti-CTLA4 led to CD4+ T cell expansion and Th17 signature in the bone microenvironment and improvement in survival. 

Dr. Sharma also stressed the importance of regulatory T cells in regulating the response to immune checkpoint blockade. She discussed how the catalytic subunit, EZH2, regulates FOXP3 transcription factor. . She described how anti-CTLA4 therapy increases EZH2 expression in CD4+ T cells from treated patients. She next investigated whether they could use EZH2 inhibitor to augment the response to immunotherapy. Mechanistically, she found that the EZH2 inhibitor decreased FoxP3 expression and increased interferon gamma expression in CD4 T cells.

In addition to the signaling pathways and cell types driving immune responses, Dr. Sharma also discussed novel immune checkpoints. She observed in prostate cancer models that expression ofPD-1, PD-L1 and VISTA immune checkpoints increased in response to ipilimumab administration, and that expression of these immune checkpoints is not seen until ipilimumab is administered. Specifically, she observed VISTA and PD-L1 expression on CD68+ macrophages,suggesting a rationale for designing immunotherapies that target the myeloid lineages.

Dr. Sharma’s talk was inspirational. She clearly described her scientific process. Her cutting-edgework demonstrated the importance of a variety of immune cell types that orchestrate anti-tumor immune responses, charting the path to the next generation of immunotherapies.