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:
Harnessing Tumor Associated Macrophages for Cancer Therapy
Macrophages infiltrate nearly all solid tumors and contribute to resistance against both conventional therapies and immunotherapy. Our objective is to identify novel macrophage-specific signaling pathways and therapeutic targets that drive immunosuppression and tumor progression. To achieve this, we analyze patient-derived datasets and publicly available scRNA-seq datasets to identify macrophage-associated targets essential for tumor growth. These targets are functionally validated using shRNA, CRISPR-Cas9, and knockout mouse models. Additionally, we investigate the mechanistic roles of these targets in immune suppression and tumor progression using ATAC-seq, scRNA-seq, and proteomics. By elucidating how macrophage-driven pathways inhibit T cell activity, our research aims to uncover new strategies for reprogramming macrophages to enhance anti-tumor immune responses and improve therapeutic efficacy.
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. In our recent findings, we demonstrated that a Syk inhibitor, in synergy with an anti-PDL1 monoclonal antibody and radiation, enhances anti-tumor immunity in neuroblastoma. Furthermore, in another study, we unveiled the synergy between the FDA-approved Syk inhibitor R788 (fostamatinib) and gemcitabine in bolstering anti-tumor immune responses in pancreatic ductal adenocarcinoma. Building on these foundational discoveries, 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.
We are currently analyzing patient samples from the trial to investigate whether SYK inhibition, in combination with gemcitabine and nab-paclitaxel, modulates the TME similarly to what we observed in mouse models.
Key papers or links
New insights into SYK targeting in solid tumors - PubMed
Rac2 controls tumor growth, metastasis and M1-M2 macrophage differentiation in vivo - PubMed
Clinical Translation:
Uncovering the Role of Myeloid Derived Suppressor Cells (MDSCs) in Tumor Immune Evasion
MDSCs, classified as monocytic (M-MDSC) and granulocytic (PMN-MDSC/G-MDSC), accumulate in tumor-bearing mice and human patients, where they suppress T cell and NK cell responses. Our recent work has shown that MDSCs accumulate neuroblastoma tumors, and targeting these cells can enhance the effectiveness of immune checkpoint blockade in neuroblastoma. Using advanced genomic, imaging, and functional analyses in human samples and mouse models, we aim to elucidate how MDSCs inhibit NK cell function and explore strategies for targeting these cells to enhance NK cell-based immunotherapy. By characterizing the molecular mechanisms underlying MDSC-mediated suppression, we seek to identify novel therapeutic approaches to boost NK cell activity and improve anti-tumor responses.
