Investigating CD4+ T cell memory in cancer immunotherapy

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Project Summary/Abstract This proposal encompasses a 5-year research and training plan to support the transition of Dr. Wattenberg to an independent research career. Dr. Wattenberg’s long-term goals are to lead an independent R01-funded research program at an academic institution, conducting research focused on defining relevant cancer immunobiology. To achieve this, Dr. Wattenberg’s short-term goals are to gain expertise in the areas of mouse modeling, transcriptomics and clinical trials. These efforts will be supported by the K08 award and through mentorship provided by Dr. Gregory Beatty and a mentorship committee consisting of successful senior scientists. Additional formal training will be provided through a didactic curriculum, including workshops and courses. Research will be conducted at the University of Pennsylvania, which provides comprehensive institutional resources and a robust research environment for the training of physician-scientists. The proposal focuses on defining how immune memory in cancer is initiated and disrupted. Studies will be performed using clinically relevant mouse models of cancer and patient samples. Immune memory is crucial for durable tumor control induced by immunotherapy. However, durable tumor responses are rare in patients. Better understanding of how immune memory develops is needed to inform novel immunotherapy strategies. Preliminary data show that activation of conventional dendritic cell (cDCs) subtypes triggers immunological memory in mouse models of pancreatic cancer. Further, immunological memory in this model is dependent on CD4+ T cells and not CD8+ T cells - the prototypical effector cells of the immune system. Additional prior work shows that systemically elevated inflammatory proteins associate with poor clinical outcomes to cDC targeted immunotherapy (CD40 agonist) in patients with pancreatic cancer. Moreover, complementary studies in mouse models show the inflammatory cytokine IL-6 to associate with cDC dysregulation. These findings suggest that inflammatory proteins drive cDC dysfunction, limiting productive immunosurveillance. It is the central hypothesis of this proposal that distinct cDC subtypes coordinate CD4+ T cell memory, which is necessary for durable tumor immunosurveillance, and that cancer-associated inflammatory proteins drive T cell immune evasion by dysregulating cDC subtypes. Dr. Wattenberg will investigate this hypothesis in the following 3 aims. Aim 1. Determine the impact of cDC subtypes on tumor specific CD4+ T cell memory. Aim 2. Determine the role of CD4+ T cells in coordinating anti-tumor immunological memory. Aim 3. Define the mechanisms by which cancer- associated inflammatory proteins drive cDC fate. Successful completion of this proposal will provide fundamental insights into cancer immunobiology and identify novel immunotherapy strategies to improve outcomes for patients with cancer. Further, the mentorship and training provided by this proposal will support Dr. Wattenberg’s transition to independence leading a translational research group.