CICON24 Day 3 Recap: Advances in T Cell Tolerance, Metabolism, and the Microbiome in Cancer Immunotherapy

Day three of CICON24 continued the momentum of the previous days with an impressive lineup of talks and discussions. Building on the high standards set by the first two days of illuminating scientific exchanges, attendees were ready for another round of groundbreaking insights.  

Diane Mathis, PhD, from Harvard Medical School, gave the Willam B. Coley Lecture to open the day’s proceedings. The audience witnessed a compelling talk on thymic mimetic cells and their role in immunological tolerance. She explored the intricate process of T cell tolerance in the thymus, emphasizing the differentiation of medullary thymic epithelial cells (mTECs). Mathis discussed the dynamic role of the transcription regulator AIRE and introduced the concept of “mimetic thymic cells” that induce T cell tolerance. Her insights into the spatial relationships and peptide presentation by these cells provided a deeper understanding of immune tolerance mechanisms. 

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The first session that followed shifted the focus to exploring how metabolism and the microbiome influence immunotherapy, promising to uncover new dimensions in cancer treatment. 

Hongbo Chi, PhD, from St. Jude Children’s Research Hospital, presented on the metabolic basis of cancer and tissue immunity. He used single-cell CRISPR-mediated gene knockout studies to reveal key insights into the transcriptional regulation of cancer metabolism and tissue immunity. Dr. Chi highlighted how metabolic communication, and reprogramming can enhance T cell immunity, shedding light on strategies to reprogram T cell metabolism for improved cancer responses. 

CRI Clinical Innovator Marina Baretti, MD from Johns Hopkins University School of Medicine, shared her research on targeting tumor cells’ metabolic dependence on glutamine to enhance immunotherapy for fibrolamellar carcinoma (FLC). Dr. Baretti is leading a clinical trial combining DRP-104, a drug targeting glutamine metabolism, with the immune checkpoint inhibitor durvalumab. This approach aims to improve treatment outcomes for FLC patients, offering new hope for this rare and aggressive cancer. 

CRI Postdoctoral Fellow, Shixin Ma, PhD from the Salk Institute for Biological Studies delivered a talk on how nutrient-driven histone codes influence T cell exhaustion. Dr. Ma’s research focused on how nutrient availability impacts epigenetic changes during T cell differentiation and function. She highlighted the role of different nutrient metabolism pathways in T cell activity and exhaustion, presenting potential strategies to rejuvenate exhausted T cells in immunotherapy. 

CRI Lloyd J. Old STAR, Ping-Chih Ho, PhD, from the University of Lausanne and the Ludwig Institute for Cancer Research discussed mitochondrial stress and its impact on T cell exhaustion. His research explored how low oxygen conditions and mitochondrial damage in the tumor microenvironment led to T cell dysfunction. Dr. Ho’s findings on the role of proteasome activity and free heme in T cell exhaustion opened new avenues for therapeutic interventions. 

Following Dr. Ho was CRI Scientific Advisory Council member and CRI CLIP Investigator, Susan Kaech, PhD, from the Salk Institute for Biological Studies. Dr. Kaech discussed how immune cells adapt to different tissue environments and the metabolic interactions between immune and tumor cells. She examined lipid oxidation in liver cancer and cirrhosis, noting its role in limiting immune responses. Dr. Kaech highlighted how elevated bile acids and the enzyme BAAT contribute to T cell stress and reduced CD8 T cell infiltration in tumors, providing insights into the metabolic landscape of liver cancer. 

The afternoon sessions featured CRI Scientific Advisory Council member Jennifer Wargo, MD, from the University of Texas MD Anderson Cancer Center, who discussed the role of the gut microbiome in cancer immunotherapy. Dr. Wargo highlighted how specific microbial species, and dietary factors influence immunotherapy responses, with fiber-rich diets enhancing treatment efficacy in melanoma patients. 

Andrew Y. Koh, MD, from UT Southwestern Medical Center, discussed fecal microbiota transplants (FMT) and their potential to improve immunotherapy outcomes. He explained how different gut microbes affect immunogenic activity and detailed the impact of immune checkpoint treatments on bacterial translocation. Dr. Koh’s research on gram-negative bacteria lysates offered new perspectives on enhancing immunotherapy. 

CRI Lloyd J. Old STAR Tal Danino, PhD, from Columbia University delivered a presentation highlighting innovative research on engineering bacteria for cancer therapy. His work focuses on harnessing the unique properties of bacteria to target tumors and deliver therapeutic agents with precision.

Saman Maleki, PhD, from Western University, explored how antibiotics affect gut microbiota and immunotherapy. He discussed antibiotic-induced antimicrobial resistance, reduced T cell infiltration, and increased T cell exhaustion. Dr. Maleki also reviewed clinical trial data on melanoma patients undergoing FMT, emphasizing the role of gut microbiome modification in improving immunotherapy responses. 

As day three of CICON24 unfolded, the energy and engagement from attendees was palpable. The day’s discussions highlighted pivotal advancements in understanding how metabolism and the microbiome influence immunotherapy. Stay tuned for more insights as we continue to explore these cutting-edge developments and their implications for the future of cancer treatment.