Department of Zoology
The University of Burdwan
Department of Zoology
The University of Burdwan
Current Research
Reprogramming the TME
We study the tumor microenvironment as a dynamic ecosystem composed of tumor cells, endothelial cells, fibroblasts and immune populations, including T cells, regulatory T cells and myeloid cells. Our research aims to identify the molecular and metabolic circuits that convert the TME into an immunosuppressive niche and develop strategies to reprogram this environment from immune suppressive to immune permissive.
Particular emphasis is placed on the TYMP–TGF-β axis, tumor endothelial cells, extracellular matrix remodeling, angiogenesis and regulatory T-cell–mediated immunosuppression. We investigate how these interconnected pathways influence immune-cell recruitment, T-cell exhaustion and therapeutic resistance, with the ultimate goal of designing combination approaches that remodel the TME and improve antitumor immune responses.
Metabolic Checkpoints in Antitumor Immunity
A major focus of the laboratory is understanding metabolism as an immune-regulatory checkpoint. Tumor cells compete with immune cells for nutrients while generating metabolites such as lactate and adenosine that can suppress cytotoxic T cells and NK cells and promote regulatory immune states.
By combining targeted metabolomics, lipidomics, flow cytometry, molecular biology and single-cell transcriptomics, we aim to identify metabolic vulnerabilities that can be therapeutically targeted to restore immune-cell fitness. Recent work increasingly supports the concept that metabolic checkpoints can complement conventional receptor-based immune checkpoints and may provide new opportunities to overcome immunotherapy resistance.
Cellular Therapy
The laboratory is developing approaches to harness and engineer immune cells for cancer therapy, with an emphasis on Dendritic-cell biology.
Our research examines how the hostile tumor microenvironment affects the persistence, differentiation, cytotoxicity and metabolic fitness of therapeutic immune cells. We are particularly interested in strategies that combine cellular therapy with TME remodeling and metabolic checkpoint inhibition, thereby enabling transferred or endogenous immune cells to function effectively within metabolically constrained tumors.
This includes investigating mechanisms of CD8⁺ T-cell exhaustion, Treg-mediated suppression, immune-cell metabolic adaptation and tumor–immune cell interactions, with the broader goal of developing next-generation cellular immunotherapies capable of overcoming the barriers imposed by the tumor microenvironment.
OUR RECENT STUDIES
Our recent work uncovered a TLR7–mitochondrial ROS (mROS)–IL-12 signaling axis that strengthens dendritic cell (DC)-mediated antitumor immunity. We demonstrated that TLR7 activation in monocyte-derived DCs induces mitochondrial ROS, which promotes IL-12 production through MyD88-independent NF-κB signaling. This enhanced IL-12 response activates NK cells, increasing their IFN-γ production and tumor-cell killing. Importantly, direct DC–NK cell contact and immunological synapse formation were found to be essential for optimal NK-cell activation. In mouse tumor models, TLR7-activated DC therapy suppressed tumor growth and improved survival, while depletion of NK cells abolished these therapeutic effects. Together, these findings reveal a previously unrecognized mechanism of DC–NK cell crosstalk and provide a rationale for exploiting the TLR7/mROS/IL-12 pathway to improve DC-based cancer immunotherapy.
The Journal of Immunology, Volume 213, Issue 8, October 2024, Pages 1255–1263
We, identified thymidine phosphorylase (TYMP) as a key driver of T-cell exhaustion and resistance to dendritic cell (DC) immunotherapy in colorectal cancer. We demonstrated that targeting TYMP with tipiracil (TPI) induces immunogenic cell death, promotes DC maturation, reduces PD-L1 expression and reshapes the tumor immune microenvironment. Importantly, combining TPI with imiquimod-activated, tumor-antigen–pulsed DCs converted immunotherapy-resistant tumors into highly responsive “hot” tumors, leading to enhanced cytotoxic T-cell infiltration and durable tumor regression in experimental models. These findings highlight TYMP targeting as a promising strategy to overcome immunosuppression and improve DC-based cancer immunotherapy.
Front. Immunol., 24 August 2022, Sec. Cancer Immunity and Immunotherapy, Volume 13 - 2022
Our research revealed that blocking TGF-β signaling can make tumors more vulnerable to dendritic cell (DC)-based immunotherapy. Using an aggressive experimental lymphoma model, we showed that galunisertib (LY2157299), a TGF-β receptor-I inhibitor, synergizes with IL-15-activated DCs to markedly suppress tumor progression and improve survival. The combination reduced immunosuppressive FOXP3⁺ regulatory T cells (Tregs) and Neuropilin-1 expression while restoring DC function and promoting CD8⁺ central memory T-cell responses and IFN-γ production. These findings identify Treg fragility and enhanced memory T-cell immunity as key determinants of durable therapeutic responses and provide a potential strategy for improving cellular immunotherapy against lymphoma.