Titles and Affiliations
Chair, Immuno-Oncology Program
Director, Mark Foundation Center for Immunotherapy, Immune Signaling, and Radiation
Research area
Improving resistance to immunotherapies in breast cancer by targeting chronic inflammation.
Impact
Immunotherapy harnesses the power of the immune system to fight cancer and is one of the most significant recent advances in cancer medicine. For breast cancer, immunotherapy has demonstrated activity for certain subtypes such as triple-negative breast cancers; however, efficacy has unfortunately been lower compared to cancers such as melanoma and lung cancer. Dr. Minn is looking to uncover why breast cancer is resistant to immunotherapy, how to make it more susceptible, and to leverage this knowledge to develop novel therapeutic strategies for patients. He and his team are investigating the idea that cancer cells can mimic certain features typically associated with chronic viral infections to minimize immune-mediated attacks, similar to how viruses can evade the immune system. A large percentage of breast cancer patients have tumors that express anti-viral gene programs typically seen when normal cells are infected with a virus. He and his team hypothesize that interfering with these anti-viral signaling pathways can restore immune function against cancer cells and improve immunotherapy efficacy.
Progress Thus Far
Dr. Minn and his team have combined two types of drugs that block enzymes involved in how cells respond to inflammation and immune signals (called the interferon signaling pathway). They found that this combination altered the development of certain cancer cells that are typically resistant to immunotherapy. These resistant cells are marked by high levels of interferon-stimulated genes and are thought to be precursors of both treatment-resistant and treatment-sensitive tumor cells. To follow how these cells change over time, they used a technique called cell barcoding, which allowed them to track groups of related cells, or clones. They found that many of these clones originally came from the resistant precursor cells but could evolve into either resistant or sensitive forms. After treatment with the drug combination, many clones shifted away from resistance and became more sensitive to therapy.
To test their findings in models that more closely resemble human breast cancer, the team has further implanted these treated cancer cells into more realistic experimental models and exposed them to immunotherapy. They observed that the treated cancer cells were less likely to remain resistant and were more easily destroyed by the immune system, reducing the risk of tumor coming back. This suggests that the drug combination may prevent cancer from becoming resistant to immunotherapy in the first place.
What’s next
In the next phase of their research, the team plans to use a gene-editing tool called CRISPR to find specific genes in the cancer cells that give rise to resistance to immunotherapy. This approach could uncover new drug targets in early-stage cells that produce high levels of interferon-stimulated genes that appear to “seed” both treatment-resistant and treatment-sensitive tumors.
They’ll also use their barcoding system to track how changes in these genes affect the overall development and behavior of tumor cells over time. Ultimately, this research aims to better understand how cancer cells resist immune-based treatments and to develop new ways to block that resistance before it starts, potentially transforming how future therapies are designed.
Biography
Andy J. Minn, MD, PhD is the Chair of the Immuno-Oncology Program at Memorial Sloan Kettering Cancer Center. He is also the Director of the Mark Foundation Center for Immunotherapy, Immune Signaling, and Radiation and Project Member at the Parker Institute for Cancer Immunotherapy. He received his MD and PhD from the University of Chicago and completed his residency in radiation oncology and post-doctoral training at Memorial Sloan Kettering Cancer Center.
His laboratory is focused on understanding the regulation and function of anti-viral signaling pathways, such as interferon and pattern recognition receptors, in cancer progression, immunotherapy response, and immunomodulation. They have discovered that activation of anti-viral signaling is widespread across multiple cancer types and often involves nucleic acid sensing, endogenous RNAs, exosomes, and interferon networks. Thus, endogenous molecules that participate in “virus mimicry” are pervasive in human cancer. They are investigating how anti-viral and pattern recognition receptors are activated in cancer, both cell intrinsically and through the tumor microenvironment, and their functional significance).
