Joshi Lab
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Research
Overall, our lab is dedicated to unraveling how myeloid cells influence the tumor microenvironment and identifying strategies to target these cells in order to enhance responses to conventional therapies and immunotherapy. We utilize a diverse range of advanced techniques such as RNA-seq, ATAC-seq, single-cell transcriptomics, immune phenotyping, and systems biology approaches. These methods are complemented by the use of human patient samples and genetic mouse models of cancer (including pancreatic adenocarcinoma, lung carcinoma, and neuroblastoma) to explore the interactions between myeloid cells, other immune components, and developing tumors.
Specific research areas are detailed below:
Identification of novel signaling pathways in macrophages that control tumor growth and metastasis
Macrophages abundantly infiltrate almost every solid tumor and contribute to resistance against conventional therapy and immunotherapy. Our objective is to discover novel signaling pathways in macrophages and, ultimately, new targets that play a role in both immunosuppression and tumor growth. We screen patient sample datasets, and publicly available scRNA-seq datasets to identify novel targets related to macrophages that are essential for tumor growth. The novel targets are validated by functional genomic approaches of shRNA, CRISP-CAS9, or using Knock-out mouse models. Our lab has identified a novel macrophage-autonomous pathway involving Rac2 and Syk kinase downstream of the provisional integrins, α4β1, and αvβ3, that governs the differentiation of immunosuppressive macrophages in tumor growth and metastasis. Our recent research has underscored Syk as a new target in the field of immuno-oncology. We have demonstrated that genetic deletion of Syk in macrophages promotes a proinflammatory macrophage phenotype, restores CD8+ T-cell activity, and stimulates an antitumor immune response in solid tumors.
Key papers or links
https://pubmed.ncbi.nlm.nih.gov/31974273
https://pubmed.ncbi.nlm.nih.gov/24770346
https://pubmed.ncbi.nlm.nih.gov/25103499
Unraveling the mechanism of action of novel macrophage target genes
Another critical objective is to elucidate how macrophage-related targets function to promote immune suppression and tumor progression. To achieve this, we employ ATAC-seq, scRNA-seq, and proteomics. These studies provide insights into the mechanisms and signaling pathways through which macrophages hinder the activity of T cells and NK cells, thereby promoting tumor growth and metastasis. We have recently demonstrated that Syk plays a vital role in promoting the immunosuppressive epigenetic and transcriptional programming of macrophages. Using ATAC-seq, we have identified that Syk controls the stabilization of HIF-1/2 alpha, inhibiting T cell responses. Conversely, Syk inhibition promotes the activation of NF-ΚB, stimulating an immunostimulatory transcriptional program in macrophages to suppress tumor growth.
Key papers or links
https://pubmed.ncbi.nlm.nih.gov/31974273
https://pubmed.ncbi.nlm.nih.gov/37350973
Modulating myeloid cell or macrophage function to enhance responses to immunotherapy and conventional therapies.
The failure of most immunotherapies and conventional treatments can be attributed to the infiltration of immunosuppressive macrophages. Hence modulating the function of macrophages can improve the responses to these therapies. In our recent findings, we unveiled the synergy between the FDA-approved Syk inhibitor R788 (fostamatinib) and gemcitabine in bolstering anti-tumor immune responses in pancreatic ductal adenocarcinoma. Furthermore, in another study, we demonstrated that a Syk inhibitor, in synergy with an anti-PDL1 monoclonal antibody and radiation, enhances anti-tumor immunity in neuroblastoma.
Rohila etal, Cancer Research, 2023
Key papers or links
https://pubmed.ncbi.nlm.nih.gov/37306759
https://pubmed.ncbi.nlm.nih.gov/37350973
https://pubmed.ncbi.nlm.nih.gov/33669187
https://pubmed.ncbi.nlm.nih.gov/31018997