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 α_vꞵ₃. 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. Our studies have demonstrated that the genetic or pharmacological inhibition of Syk and/or PI3Kgamma in macrophages fosters a proinflammatory macrophage phenotype. This intervention not only restores CD8+ T-cell activity but also destabilizes hypoxia-inducible factor (HIF) under hypoxic conditions, ultimately stimulating an anti-tumor immune response in solid tumors.