Expanding Immunotherapy Efficacy by Understanding Mechanisms of Response Versus Resistance: Distinguished Scientist Moores Cancer Center Director’s Seminar Series

July 11, 2024

Moores welcomed Thomas F. Gajewski, MD, PhD to present “Expanding Immunotherapy Efficacy by Understanding Mechanisms of Response Versus Resistance,” which was co-hosted by Moores Director, Diane Simeone, MD and Moores Associate Director for Basic Science, J. Silvio Gutkind, PhD, who, along with UC San Diego Health, are eager to understand the mechanisms of checkpoint blockades, their limitations, and the ability to leverage this knowledge to propel advancements in cancer care. 

Dr. Gajewski is a Professor of both Pathology and Medicine, the Ben May Institute Program Leader, and a Member of the Immunology and Cancer Program at the University of Chicago, where he earned his BS, MD, and PhD. He researches more effective strategies for leveraging the immune system to combat cancer, which are tailored to the specific methods each tumor employs to evade detection. 

Dr. Gajewski began his presentation by outlining the two categories of immune escape: T-cell inflamed (hot) and non-inflamed (cold) tumor microenvironments.  

For T-cell inflamed tumor microenvironments, he addressed the question of why these tumors even exist, if the body has T-cell responses against them. He explained that these T cells are held in check by negative regulation, whereas non-T-cell-inflamed tumors are “immune deserts.” 

Dr. Gajewski then presented how the effectiveness of certain immunotherapy drugs for various cancers correlates with the initial presence of a T-cell inflamed tumor microenvironment.  

He explained that this correlation “made us start to think about mechanisms of primary resistance.”  The lack of antigens is not the problem—it has something else to do with the biology of the tumor or the biology of the host. To understand the mechanisms of response versus resistance, Dr. Gajewski explained that he and his team examined interpatient heterogeneity that regulates the T-cell inflamed tumor microenvironment, and they narrowed the cause to one of three things: tumor cell somatic differences, environmental differences, or host germline genetic differences. 

To understand the tumor cell somatic differences, Dr. Gajewski studied the activation of cancer cell-specific intrinsic β-catenin, PTEN loss, and DNA repair mechanisms. For the environmental differences, he and his team examined the commensal microbiota. Dr. Gajewski explained how the composition of the gut microbiome is associated with certain immunotherapy drug efficacy in metastatic melanoma patients.  

Dr. Gajewski concluded his presentation by addressing the regulation of the tumor microenvironment through examining the enzymes involved in signaling pathways within cells—particularly those related to cell growth and differentiation. 

By examining three different dimensions of tumor data that regulate the T-cell tumor microenvironment, he and his team found that they all affect some sort of white blood cells, called myeloid cells, that play a key role in the immune system, by fighting infections and promoting inflammation. “We were focused on understanding responders,” he explained. “Now it is crucial we also look at non-responders.”