We are dedicated to uncovering new ways to target and leverage the immune system for cancer therapy.
In cancer, myeloid cells are among the most common immune cells to infiltrate tumors, and frequently exert immunosuppressive and pro-tumorigenic functions. However, myeloid cells are pliable and exhibit the potential for tumor-cytotoxicity via a variety of pathways including phagocytosis, reactive oxygen species generation and cytokine production.
We have found that combined activation of distinct myeloid signaling pathways can drive eradication of pancreatic tumors, which are resistant T cell checkpoint inhibitors. However, the molecular mechanisms underlying the anti-tumor activity generated by myeloid activation therapy remain ill-defined.
We are now using transgenic mouse models of pancreatic cancer, as well as newly designed tools for the study of phagocytosis, to define the molecular mechanisms driving tumor-cytotoxic myeloid cells. Additionally, we are developing unbiased CRISPR screening approaches to study the role of myeloid pathways in cancer. The goal of these studies is to identify druggable targets in myeloid cells for cancer therapy.
Crucial for long-lasting anti-tumor activity is the formation of immunological memory. However, many tumors, including pancreatic cancer show profound resistance to cancer immunotherapy.
Historically, FDA approved immune activating drugs (e.g., checkpoint inhibitors and chimeric antigen receptor T cell therapy) have focused on leveraging cytotoxic CD8 T cells, which are excluded from immunotherapy resistant tumors. However, CD4 T cells, commonly classified as ‘helper’ T cells, can also directly elicit tumor control. Indeed, CD4 T cells can directly impact tumor cell growth, and coordinate recruitment of myeloid effector cells to the tumor microenvironment. Further, CD4 T cells target distinct antigens, beyond those targeted by CD8 T cells, and effective use of CD4 T cells may extend productive T cell immunosurveillance to additional tumor types.
Using models of pancreatic cancer, which are resistant to immune checkpoint blockade, we are now studying how memory CD4 T cells form and coordinate immunological memory. We are incorporating spatial transcriptomics and in vivo functional studies to define physical and paracrine cellular interactions in the tumor microenvironment. These studies aim to inform the design of therapeutic strategies targeting CD4 T cell – myeloid cell interactions in cancer.
Tumor cells exist within an ecosystem of neighboring stromal and tumor-associated cells. We previously found that tumor cells defined by distinct cellular neighborhoods coordinate outcomes in patients with surgically resectable pancreatic cancer. By manipulating myeloid signaling pathways we are able to alter the cell neighborhoods tumor cells exist in. We are now seeking to define at the molecular level how tumor cells respond to distinct cellular environments, especially those that are enriched for myeloid effector cells.
We have developed customizable CRISPR screening tools to study the genetic dependencies of tumor cells in vivo in the context of distinct tumor microenvironments. We are currently focused on defining how innate immune signaling pathways in tumor cells contribute to resistance and sensitivity to immunotherapy.