immunosuppression
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Targeting VIP–VPAC Signaling to Reverse Immune Exclusion and Enhance Immunotherapy Response in Pancreatic Cancer
Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal cancer that is largely unresponsive to chemotherapy and current immune checkpoint blockade drugs, highlighting a critical need for the development of innovative therapeutic strategies. This R01 proposal targets vasoactive intestinal peptide (VIP), an immunosuppressive neuropeptide overexpressed in PDAC, which signals through VIP receptors (VPAC) on cancer cells, T cells, and myeloid cells within the tumor microenvironment. Based on our recent success in developing selective and potent VPAC receptor antagonists, we hypothesize that blocking VPAC signaling will reverse immunosuppression in the PDAC TME by reducing immune checkpoint expression, enhancing chemokine-driven infiltration of cytotoxic T cells, and disrupting immunosuppressive interactions between T cells and myeloid cells, ultimately leading to durable anti-cancer immunity. We propose three specific aims to explore the immunosuppressive roles of VPAC signaling in PDAC. Aim 1 will identify the primary sources of VIP in PDAC tumors and characterize the effects of VPAC signaling on immune cell function and phenotype within the tumor microenvironment. Aim 2 will investigate how VPAC signaling influences immune cell migration into tumors by modulating chemokine receptors and directional signaling. Aim 3 will determine how VPAC signaling regulates interactions between T cells and immunosuppressive myeloid cells, particularly tumor-associated macrophages, and the resulting impact on anti-cancer immune responses and immunological memory. Our preliminary findings indicate that combined inhibition of VPAC signaling and PD-1 significantly enhances the regression of PDAC tumors in multiple mouse models, generating lasting protective immunity in cured mice without triggering autoimmune responses. We will use novel methods to pursue our aims, including inducible genetically engineered mouse models (GEMM) of PDAC, long-acting VPAC antagonists engineered with immunoglobulin Fc domains to improve their plasma half-life, and advanced microfluidics technologies to analyze immune cell movement within tumors. Animal experiments will be used to validate the translational potential of observations from in vitro organoids and microfluidic experiments. The GEMM and orthotopic mouse models of PDAC are necessary to provide critical insights into the 3-D structure of the TME and tumor regression in response to our novel immunotherapy. This research will be conducted by a multidisciplinary team with complementary expertise that will clarify the therapeutic potential of VPAC signaling inhibition in PDAC using sophisticated experimental tools and single-cell RNA sequencing. Ultimately, these findings could significantly improve the development of immunotherapeutic strategies for PDAC, potentially enhancing patient outcomes in pancreatic cancer and other malignancies expressing high VIP levels.
Th17 plasticity in rheumatoid arthritis
ABSTRACT The objective of this grant application is to explore the plasticity of Th17 in arthritis. Interleukin-17A (IL-17A) producing Th17 are present in the blood and synovium of patients with rheumatoid arthritis (RA). However, targeting of IL17A has been insufficient to control joint inflammation of RA patients. One potential scenario is that in the context of worsening RA joint inflammation, Th17 undergo conversion into pathogenic IL17A- negative cell populations, collectively called exTh17. The conversion of Th17 into exTh17 has been documented in the context of neuroinflammation, colitis, and infection. However, the occurrence of Th17 plasticity in autoimmune arthritis and its potential role in perpetuating synovial inflammation has remained mostly unexplored. We generated a novel fate-mapping mouse model of autoimmune arthritis, which allows to follow the conversion of Th17 into exTh17, and collected preliminary data suggesting that Th17 undergo significant loss of IL17A expression and conversion into exTh17 in the context of synovial inflammation. We also identified exTh17 signatures which might help exTh17 perpetuate joint inflammation despite their loss of IL17A expression. Here our objective is to further elucidate intrinsic (Aim 1) and extrinsic (Aim 2) mechanism of Th17-exTh17 conversion and exTh17-mediated joint inflammation, and explore the potential role of exTh17 in RA interstitial lung disease (ILD, Aim 3) a feared and often untreatable complication of established RA. Our long-term goal is to leverage the knowledge of local immune cell phenotypes and how they change at various stages of disease to enable stage-specific and personalized therapies of RA which minimize non- specific immunosuppression.
Immunosuppression for Parkinson's disease - a new therapeutic strategy?
Caroline Williams-Gray is a Principal Research Associate in the Department of Clinical Neurosciences, University of Cambridge, and an honorary consultant neurologist specializing in Parkinson’s disease and movement disorders. She leads a translational research group investigating the clinical and biological heterogeneity of PD, with the ultimate goal of developing more targeted therapies for different Parkinson’s subtypes. Her recent work has focused on the theory that the immune system plays a significant role in mediating the heterogeneity of PD and its progression. Her lab is investigating this using blood and CSF -based immune markers, PET neuroimaging and neuropathology in stratified PD cohorts; and she is leading the first randomized controlled trial repurposing a peripheral immunosuppressive drug (azathioprine) to slow the progression of PD.
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