About the Lab
The Joshi lab investigates the cellular and molecular mechanisms regulating the recruitment, differentiation, and activation of myeloid cells in solid tumors. Immunosuppressive myeloid cells and macrophages release various cytokines to promote immunosuppression and dampen anti-tumor immune responses, contributing to the failure of immunotherapy, chemotherapy, and radiation therapy. Utilizing genetic mouse models of pancreatic ductal adenocarcinoma and neuroblastoma, along with human patient samples, our lab studies myeloid cell interactions with other immune cells and developing tumors. Our goal is to identify novel strategies for reprogramming these myeloid cells, ultimately enhancing responses to current therapies in solid tumors.
Our lab has uncovered a novel, macrophage-autonomous pathway that involves Rac2 and Syk kinase downstream of provisional integrins, α4ꞵ1 and αvꞵ3. This pathway exerts control over immunosuppressive macrophage differentiation in tumor growth and metastasis. Recent findings from our research highlight Syk as a promising immuno-oncology target, showcasing its pivotal role in regulating macrophage-mediated immune suppression and inhibiting anti-tumor immunity in neuroblastoma and pancreatic ductal adenocarcinoma. We have identified innovative strategies to convert pro-tumor macrophages into anti-tumor macrophages and have discovered novel targeted agents that have progressed to early-phase clinical trials for cancer treatment. One such example is Syk inhibition. We recently initiated a Phase 1b clinical trial (NCT06639724) evaluating the Syk inhibitor R788 (fostamatinib) in combination with gemcitabine and nab-paclitaxel for patients with resectable pancreatic cancer.