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Dr. David DeNardo Explores How the Tumor Microenvironment Affects Immune Responses to Cancer

Photo of Dr. David DeNardo

David DeNardo, Ph.D., is a Professor of Medicine and Co-Director of the Tumor Immunology Program at the Washington University St. Louis, School of Medicine. 

His research team is working to understand why responses to cancer immunotherapy vary among patients. In studying and uncovering mechanisms of cancer immunology, Dr. DeNardo aims to identify strategies that can be translated into the clinic to re-activate a patient’s antitumor immunity.  

In this interview, he shares his advice for trainees, his immuno-oncology research, and opportunities in the development of immunotherapies.

What advice do you give to trainees in your laboratory? 

I encourage my trainees to follow their passion. If they really love something, they will find their work invigorating and engaging, and in the long-term more fulfilling. 

Other than that, I encourage my trainees to take risks and to ask difficult questions where “yes” and “no” are both equally interesting outcomes. These are often some of the really satisfying answers. 

It’s important to remember that experiments give information no matter the intended outcome. A “no” result can be one of the most important discoveries you make. An abject failure in terms of what your hypothesis was can be informative because it gives you the opportunity to change your point of view and consider your hypothesis in a different light. 

Could you describe your antitumor immunity and cancer immunotherapy research? 

Cancer builds what we call the tumor microenvironment. This is the house that the cancer lives in, and it can shield cancer from the host immune system. What we try to do is understand how we can overcome this house and restore proper host immune system function with the end goal of developing new therapies and improving existing therapies for patients. 

What do you think are some opportunities in the preclinical development of new cancer immunotherapy approaches?

First is the development of new model systems. Our current models do not give us enough fidelity on how human cancers develop, how they escape the immune system, and the factors determining response and non-response to immunotherapy. This is an area that we as scientists need to continue to improve.

Second is leveraging the high volume of detailed data from human cancer patients to understand how the immune system interacts with tumors. It is challenging to figure out at times but critical. Careful studies in human tissue are often critical to allow us to develop new hypotheses on how the tumor and immune system co-evolve. 

Based on your personal experiences as an investigator who runs a basic and translational research lab, what is the significance of basic cancer research? 

In patients with immunotherapy-resistant cancer, we do not know how to leverage the immune system effectively to treat them. With a fundamental understanding of how the immune system works and how it co-evolves with cancer, we can begin to answer this question. 

Without this basic science knowledge, translational researchers are shooting in the dark and making hypotheses without the foundations of science. When your clinical hypothesis does not pan out, basic research can allow you to go back, readdress mechanisms at play, and reform your hypothesis on how to move forward clinically. 

Can you share an overview of your recent Cancer Discovery study and describe how this work is being translated into the clinic?

Radiation therapy can effectively control local tumor growth in patients with pancreatic cancer; however, it does not always prevent the emergence of metastasis. This type of abscopal effect (in which the radiation treatment inhibits the growth of the targeted cancer but also suppresses the development of tumors elsewhere in the body) requires priming of the immune system, specifically T cell immunity.

My lab identified a molecular pathway in preclinical models of pancreatic cancer that involves a specific kinase, known as focal adhesion kinase (FAK), that promotes a tumor-supportive microenvironment by blunting anti-tumor immune responses after radiation therapy. 

Our basic and preclinical studies showed that FAK inhibition improves the efficacy of radiation therapy and induces anti-tumor immunity. 

Together with radiation oncologist, Dr. Hyun Kim, we sought to determine if this observation holds true in human pancreatic cancer patients. To accomplish this, we are testing if a FAK inhibitor plus standard of care radiation therapy would 1) be more effective and 2) would promote a better overall immune response to radiation therapy. Our hope is that by stimulating the anti-tumor immune response with the combination therapy, patients will have long-term metastasis-free survival.


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