My research focus is on the study of the interaction of inflammatory leukocytes and fibroblasts with tumor cells in human lung and ovarian tumor microenvironments by using an immunodeficient tumor xenograft model. This model includes the tumor, the tumor-associated stromal fibroblasts and the inflammatory cells, including lymphocytes.

In my lab, I work with a research team of students and postdoctoral fellows to study the immune response of cancer patients to their tumors. Our data indicate that tumor-specific lymphocytes, once present in the tumor microenvironment, become hyporesponsive and fail to attack and kill tumor cells. This hyporesponsiveness is due to an arrest or checkpoint in the T cell receptor (TCR) signaling machinery. Our studies are designed to gain a better understanding of the molecular events that are responsible for signaling arrest. We also aim to determine ways to prevent, or even reverse the TCR signaling arrest, for example, by eliminating or blocking the lipid-mediated disruption of the TCR signaling cascade.

Using the tumor xenograft models, we have structurally identified the immunoinhibitory factors present within the tumor ascites fluids and determined the mechanism by which they arrest the TCR signaling. We found that these cells fail to respond to activation signals due to the disruption of the TCR signaling cascade that occurs at, or just proximal to the activation of PLC-γ. An identical TCR signaling arrest also occurs in human T cells found in chronic inflammatory tissues. Using the xenograft models, we established that a local and sustained release of IL-12 into the tumor microenvironment activates the quiescent tumor-associated T cells to produce and secrete IFN-γ, which mobilizes an immune-mediated eradication of the tumor.

We recently found that lipids present within the ascites fluids of human ovarian tumor mediate a reversible arrest in the TCR signaling pathway of ovarian tumor-associated T cells. We have now determined that extracellular microvesicles (exosomes) isolated from human ovarian tumors and tumor ascites induce a rapid and reversible arrest in the T cell signaling cascade. The T cell inhibition is causally linked to phosphatidylserine that is expressed on the outer leaflet of the exosome membrane. The target of this arrest is diacylglycerol, and the induced suppression is blocked or reversed by diacylglycerol kinase inhibitors. This suggests a likely mechanism by which the tumor-associated exosomes arrest both CD4+ and CD8+ T cell activation.

The ability to eliminate or block/reverse that inhibitory activity of the exosomes represents a potentially viable therapeutic target for enhancing patients’ antitumor response and for preventing the loss of function of CAR-T cells upon entry into the tumor microenviroment.

These findings will provide valuable information in designing new immunotherapeutic strategies for patients with advanced cancer.