Jashodeep Datta, M.D., a hepatobiliary and pancreatic surgical oncologist at Sylvester Comprehensive Cancer Center at the University of Miami Miller School of Medicine, has been awarded a $150,000 grant by the Elsa Pardee Foundation to advance his research in pancreatic cancer.
Named after the late Elsa U. Pardee, whose life was taken by cancer, the grant was established to promote the cure and control of cancer. The foundation annually awards one-year grants to researchers at academic institutions in the U.S. who are new to the field of cancer research or are established research investigators examining new approaches to cancer cure.
“I was thrilled to learn that I had been selected as a recipient of the Elsa Pardee Foundation grant,” Dr. Datta said. “This is a highly competitive foundation grant awarded for ‘high-risk ‘high-reward’ research across cancer disciplines. The foundation receives a large number of applications every year and funds a small fraction of these.”
Dr. Datta’s research has been focusing on understanding the genotype-phenotype chasm in pancreatic cancer. He specifically focuses on the intersection between high-risk genomics that represents the molecular foundation of this lethal disease and how particular genotypes orchestrate immunologic events that govern immunosuppressive crosstalk between different constituents of the tumor microenvironment, as well as T-cell dysfunction, which render pancreatic cancer resistant to chemotherapy and immunotherapy.
How Mutations Work Together
“We have defined cooperativity between Ras and p53 mutations, two genetic mutations known to be associated with worse survival in many gastrointestinal cancers including pancreatic cancer, as a prototype of high-risk genomics,” Dr. Datta said. “In Ras-p53 cooperative pancreatic cancer, myeloid-derived suppressor cells (or MDSCs) — a specific component of the innate immune system — have emerged as the key culprit controlling inhibitory tumor-stromal-immune crosstalk.”
Dr. Datta’s research implicates MDSC-derived TNFa, a substance in the body that causes inflammation, as a master regulator of immune exclusion and T-cell dysfunction in Ras-p53 cooperative pancreatic cancer. His work further shows that inhibition of TNFa signaling in MDSCs invigorates T-cell infiltration and rescues the suppression of T-cell cytolytic activity by MDSCs in a TNFa-dependent manner.
“We believe that unraveling and targeting these tolerogenic mechanisms in MDSCs is of paramount importance, since they can overcome immune exclusion, unleash anti-tumor immunity, overcome therapeutic resistance, and revolutionize treatment for pancreatic cancer patients,” Dr. Datta said.
With the grant, Dr. Datta and his team are looking forward to delving into the specific mechanisms that govern the cellular fate of MDSC-derived TNFa and how targeting these mechanisms might disrupt their inhibitory effects on T-cell function and suppressive tumor-stromal-immune crosstalk in the pancreatic tumor microenvironment.
Reshaping the Therapeutic Landscape
The support from the Elsa Pardee Foundation will develop novel adoptive transfer models to dissect the specific contributions of MDSC-intrinsic mechanisms on T-cell function, tumor growth, and sensitivity to immunotherapy. It will further determine if targeting MDSC-derived TNFa will overcome T-cell dysfunction to sensitize pancreatic cancer to immunotherapy. Although the proposed research is by definition “high risk,” it has the potential to be paradigm-shifting in shaping the therapeutic landscape of pancreatic cancer.
“As a surgical oncologist and translational cancer immunology researcher, my ultimate goal is to deliver discoveries we make at the research bench to the patient’s bedside," Dr. Datta said. “Therefore, we hope that this proposal will impact the clinical treatment of pancreatic cancer by discovering a multi-pronged therapeutic strategy to disrupt the tolerogenic MDSC-derived signaling that governs therapeutic resistance in this disease and translate these discoveries to pancreatic cancer patients via innovative clinical trials at Sylvester Comprehensive Cancer Center and beyond.”
As a foundation for his success Dr. Datta acknowledges support from Sylvester and the Department of Surgery, his mentor Nipun Merchant, M.D., professor of surgery and associate director of translational research at Sylvester, as well as his research team at the Miller School, including Anna Bianchi, cancer biology Ph.D. candidate, Iago De Castro Silva, M.D., surgery research associate, and Nilesh Deshpande, post-doctoral fellow.