Researchers at the Sylvester Comprehensive Cancer Center at the University of Miami Miller School of Medicine have shown they can bypass a key mechanism in castration-resistant prostate cancer (CRPC) and potentially make immunotherapies more effective. By infusing nitric oxide (NO) into animal models, the team shrank tumors and paved the way for possible combination therapies. The study was published in Nature Cell Death & Disease.
We have shown that by treating these animals with exogenous nitric oxide, we reduce oxidative stress, sensitize tumors to a therapy that blocks the CSF1 receptor, and rebalance the immune components of the tumor microenvironment. By doing this, we can reduce the burden of these highly resistant tumors.”
Himanshu Arora, Ph.D., Assistant Professor at Sylvester and the Desai Sethi Institute of Urology
Many prostate tumors initially respond to antihormonal therapies but, over time, can develop resistance. Researchers have been looking at therapeutic alternatives, including immunotherapies, but with mixed results. One potential target is the CSF1 receptor, which plays an important role in choosing which macrophages populate the tumor microenvironment.
“The CSF1 receptor regulates macrophage polarization,” said Dr. Arora. “In this context, M1 macrophages destroy tumor cells while M2 macrophages suppress the immune response. But mutations can upregulate CSF1, creating more M2 cells and helping the tumor microenvironment to grow and thrive.”
Identify why CDF1 inhibition may fail
Scientists have tried to block CSF1 and regain control of tumors, but that approach has so far fallen short, suggesting something more is at play.
In the study, the team identified several reasons why CSF1 inhibition may fail. One problem was increased oxidative stress in the tumor microenvironment, which counteracts CSF1 inhibition by altering the cellular balance between oxidant molecules and antioxidants.
Even more important, the researchers showed that an enzyme called nitric oxide synthase 3 (NOS3) loses function, no longer produces NO, and sets off a chain of events. Without NO, the CSF1 receptor cannot be nitrosylated, a protein modification that critically affects its function. As a result, the non-nitrosylated protein does not properly govern the balance between M1 and M2 macrophages, increasing the cancer microenvironment and helping tumors resist CSF1 inhibition.
The team found that by infusing NO, they could reduce oxidative stress and support CSF1 nitrosylation, improving CSF1 inhibition and shrinking prostate tumors.
“This paper is very important because it helps us understand this important pathway and has definite implications for treatment,” said Joshua Hare, MD, the Miller School’s chief scientific officer and professor of molecular and cellular pharmacology. “Allowing nitrosylation on this protein has a dramatic effect on the treatment of this prostate cancer model and is extremely exciting.”
Additional research
This work is just the beginning for Dr. Arora. He is also working with Associate Professor Fangliang Zhang, Ph.D., to understand how nitrosylation and another protein modification, called arginylation, affect immune resistance in high-grade prostate cancers. In addition, Arora’s lab is investigating how these mechanisms may influence the effectiveness of other immunotherapies, such as PD-L1 checkpoint inhibitors.
“We can combine these immunotherapies with NO to make them more effective,” Dr. Arora said. “We look forward to beginning preliminary phase 1 clinical trials to test these therapies in combination and hope to improve patient outcomes.”
Study partners included clinical investigators Ranjith Ramasamy, MD, Thomas A. Masterson, MD, and Sanoj Punnen, MD; postdoctoral researchers Fakiha Firdaus, Rehana Qureshi and Raul Dulce; and medical students and fellows Manish Kuchakulla, MD, Yash Soni and Khushi Shah.
“This paper is the culmination of hard work and persistent input from the entire team,” said Dr. Arora. “We are deeply grateful for the continued support we have received from Sylvester, the Desai Sethi Institute of Urology, and the American Cancer Society, which enabled us to conduct this comprehensive research.”
Source:
University of Miami Health System, Miller School of Medicine
Journal reference:
Firdaus, F., et al. (2022) S-nitrosylation of the CSF1 receptor increases the efficacy of CSF1R blockade against prostate cancer. Cell death and disease. doi.org/10.1038/s41419-022-05289-4.