Our lab is focused in understanding the underlying mechanisms of how the tumor microenvironment is shaped and is changed in response to cancer immunotherapies. Furthermore, the lab aims to develop new and improved diagnostic, prognostic, and therapeutic tools to detect, diagnose, treat, and prevent cancer. Our research aims are fourfold: (1) to develop methods for non-invasive monitoring of immune responses; (2) to design and engineer novel CAR T cells; (3) to investigate changes in the tumor microenvironment (TME) in response to treatment; and (4) to explore how to reshape the TME to a more pronounced anti-tumor status and develop tools to realize this possibility. In the long term, our goals are to help better understand dynamics of immune responses, to investigate what is behind the heterogeneous response to cancer immunotherapy, and to help understand what causes an immunosuppressive or an anti-tumor TME. These are essential for developing more effective therapies, more effective methods for early detection of cancer, and new prognostic modalities.
Having established robust methods of performing immuno-PET, our experiments have broken new ground and laid the groundwork for more sophisticated ways of exploring the TME. We can now predict, in the B16 melanoma model, the response to immunotherapy based on differences in distribution of CD8 T cells (1). Furthermore, using single-cell RNAseq performed on the immune infiltrating cells in responder and nonresponder animals, we have discovered that an effective response to checkpoint blockade is accompanied with a general reprogramming of the myeloid cells in the TME. The responders exhibit a dominant population of macrophages with an M1-like signature, whereas the immune cells in the nonresponders display an immunosuppressive M2-like status (2). We are now proposing to develop novel imaging platforms that enable monitoring dynamics of engineered antigen-specific T cells and CAR T cells. Developing such platforms are completely new, and if successful, would be a breakthrough on the application and assessment of adoptive cell therapy. In addition, to develop more effective therapies we are aim to design novel CAR T cells and efficient scaffolds capable of targeting tumors and releasing immune modulating agents in the TME that are otherwise systemically toxic.
Furthermore, and in collaboration with Weinberg lab at the Whitehead Institute/MIT, we are exploring the role of Epithelial-to-Mesenchymal Transition (EMT) in shaping the breast tumor immune microenvironment and whether it affects the response to checkpoint blockade therapies. The TME of breast carcinomas is enriched with highly immunosuppressive immune cells and their numbers in the stroma increase as carcinomas gain aggressive properties. However, the mechanisms that regulate the interplay between carcinoma cells and immune cells that lead to the assembly of immunosuppressive TME are unknown. Carcinoma cells that have activated the EMT gain stem-like characteristics and mount refractory responses to several drug and chemotherapeutic treatment regimens. We have demonstrated that this process also alters the interaction of carcinoma cells with tumor infiltrating immune cells (3). Specifically, mesenchymal tumors that express features of the EMT recruit immunosuppressive cells to the tumor stroma, display elevated levels of immunoevasive markers and are resistant to elimination CTLA4 blockade relative to their more epithelial counterparts. However, mechanism by which tumors displaying features of the EMT mount immunosuppressive and immunoevasive maneuvers remains largely unknown. Therefore, we aim to determine the molecular mechanism underlying EMT-mediated immunosuppression and the refractory response of mesenchymal tumors to checkpoint blockade therapy.
Reference: 1. Rashidian M, et al. (2017) Predicting the response to CTLA-4 blockade by longitudinal noninvasive monitoring of CD8 T cells. J Exp Med. doi:10.1084/jem.20161950. 2. Rashidian M, et al. (2019), “Immuno-PET identifies the myeloid compartment as a key contributor to the outcome of the anti-tumor response under PD-1 blockade”, PNAS, USA, 2019. 3. Dongre A, Rashidian M, et al. (2017) Epithelial-to-mesenchymal Transition contributes to Immunosuppression in Breast Carcinomas. Cancer Res. doi:10.1158/0008-5472.CAN-16-3292.