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With help from a National Cancer Institute (NCI) grant, OSUCCC – James scientists will study the biological causes of resistance to immunotherapy in patients with non-small cell lung cancer (NSCLC), the leading cause of cancer death worldwide.

Principal investigator for the three-year, $564,408 Transitional Career Development Award is Martin Benej, PhD, a research scientist in the Cancer Biology Program at the OSUCCC – James with a pending appointment as a tenure-track assistant professor in the Ohio State College of Medicine’s Department of Molecular Medicine and Therapeutics.

The project abstract states that NSCLC is an aggressive disease with a poor prognosis due to high rates of treatment resistance and disease recurrence. Treatment has been enhanced in the past decade by immunotherapy, particularly the use of programmed cell death 1 (PD-1) immune checkpoint inhibitors (ICB). PD-1 inhibitors block the activity of PD-1 proteins, which typically prevent T cells in the immune system from attacking cancer cells, allowing them to grow and spread.

But Dr. Benej and colleagues note that, although PD-1 inhibitors have a promising clinical profile, they result in long-term disease control in less than 25% of patients with NSCLC, and the reasons for this heterogeneous (varied) response are not fully understood.

“Understanding the mechanisms of treatment resistance is essential to addressing the dire need for novel therapies to target refractory (treatment-resistant) disease in NSCLC tumors,” Dr. Benej says.

One such mechanism, he adds, is called hypoxia, or decreased oxygen levels within the tumor microenvironment. “Experimental evidence shows that low oxygen may contribute to the poor response to treatment of many NSCLC tumors – which are among the most hypoxic tumor types.”

In this project, he continues, researchers will investigate the role of tumor hypoxia as a modulator of immune privilege in mouse models of NSCLC.

“Immune privilege” is the body’s means of protecting its vital organs, such as the lungs, from the possibly harmful effects of an immune response.

“There is mounting evidence that a hypoxic tumor microenvironment supports the immune privilege of NSCLC tumors, thus limiting the therapeutic potential of PD-1 inhibitors,” Dr. Benej says, adding that he and colleagues will work to better understand this process and identify ways to offset hypoxia within the tumor microenvironment in hopes of improving patient response to immunotherapy.

“The findings of this research are expected to provide the foundation for future studies of how crosstalk between the tumor microenvironment and dysregulated T-cell function dictates the outcome of immunotherapy in NSCLC,” Dr. Benej says, “providing hope that therapeutic reversal of hypoxia can sensitize NSCLC tumors to PD-1 inhibitors.”