Resistance to immunotherapy can arise when cancer cells acquire genetic mutations that make them resistant to immune killing. We have identified that tumors with specific resistance mutations recruit unique populations of immune cells, called myeloid cells, which can prevent the immune system from killing the tumor. As proof of principle that myeloid cells contribute to immunotherapy resistance, we can overcome resistance by specifically targeting myeloid cells in tumors with one of the most commonly acquired resistance mutations.

How can we overcome resistance mediated by loss of antigen presentation?

Loss of antigen presentation genes by tumor cells is one of the most commonly acquired mutations associated with resistance to immunotherapy. These mutations allow the cancer cells to evade recognition and killing by CD8+ T cells. The Miller lab is exploring alternative immunotherapy approaches to overcome resistance mediated by loss of antigen presentation genes.  By targeting other immune cells, we hope to develop strategies to fight cancer that do not rely upon CD8+ T cell mediated killing.

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How do specific tumor resistance mutations alter the immune microenvironment?

Precision medicine has revolutionized how we approach cancer patients – treating different patients with different targeted therapies, depending on their unique tumor mutations. Unfortunately, we have not been able to apply the same level of personalization to immunotherapy treatment. We simply do not understand how different tumor mutations change the immune response against the tumor. By studying genetically characterized human samples and mouse models, we are working to understand the different patterns of immune response against tumors. Our goal is to design personalized immunotherapeutic strategies based on a patient’s tumor mutations or tumor-infiltrating immune cells.

How do myeloid cell states contribute to resistance?

Immune cells of the myeloid lineage regulate nearly all aspects of the immune response, and yet they remain poorly understood. Our goal is to dissect the complicated biology of these cells to understand how they regulate the anti-tumor immune response. To accomplish this goal, we are building new technologies and reagents to interrogate myeloid cell development and functions in the tumor. Using the latest in vivo CRISPR screening approaches, single-cell genomic analyses, and functional assays, we hope to develop novel therapeutics targeting myeloid cells.

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