Mechanism of Checkpoint Protein Regulation Identified, Suggesting New Approaches to Boosting Cancer Immunotherapy

May 01, 2020 | Biotechnology

Reading time: 4 minutes

Sourced by Lab.Equipment from GEN – Genetic Engineering and Biotechnology News, here is this week's Biotechnology industry news for you:

Scientists at the University of Texas (UT) Southwestern Medical Center used CRISPR-based screening to help identify a mechanism by which cancer cells can regulate the production of a protein that suppresses immune system responses against the tumor. The team’s combined studies in human lung cancer cells and in mice found that blocking heme production activated the integrated stress response (ISR), which led to increased production of programmed death ligand 1 (PD-L1) and suppression of antitumor immunity. PD-L1 is a key target of immunotherapy drugs known as checkpoint inhibitors.

The scientists also showed that the effects of heme inhibition could be replicated by overexpressing a single gene, eIF5B, which they subsequently found is upregulated in human lung cancers. Headed by UT Southwestern associate professor Kathryn A. O’Donnell, PhD, the team said their results suggest that eIF5B functions as an oncogene, and that the findings could point to new approaches to boosting the effectiveness of anticancer immunotherapy. “… these findings revealed an unanticipated mechanism of immune checkpoint activation in lung cancer with important therapeutic implications,” they concluded in their published paper in Nature Cancer, which is titled, “eIF5B drives integrated stress response-dependent translation of PD-L1 in lung cancer.”

Cancer cells, including non-small cell lung cancer (NSCLC), frequently express high levels of PD-L1, a ligand of the programmed cell death protein 1 (PD-1) receptor on T cells, allowing tumors to directly suppress the host immune response by inhibiting T cell proliferation and function, the authors explained. Antibody-based immune checkpoint inhibitor drugs that block PD-L1 have yielded “remarkable results,” they continued, and anti-PD-1 immunotherapy is approved as first-line therapy for lung cancer... More of this in the GEN – Genetic Engineering and Biotechnology News Blog.

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