Research Projects

Glioblastoma (GBM) is the most lethal primary brain tumor. Despite multimodal therapy (safe surgical resection followed by radiotherapy and concomitant chemotherapy), recurrence is inevitable, leading to dismal survival of less than 15 months (Mahaddalkar et al. 2025). Thus, to target GBM and to prevent recurrence, newer strategies are urgently required. Recently, immunotherapy has emerged as a transformative approach for cancer treatment with immune checkpoint inhibition (ICI), showing promise in multiple malignancies (Kim et al., 2020). Unfortunately, current immunotherapies in GBM have not been very successful. This failure has been attributed to the presence of a heterogenous tumor immune microenvironment (TIME), predominantly populated by immunosuppressive cells like tumor associated macrophages (TAM; comprised of CD11b+veCD14+veHLA-DR+veCD19+ve M1 and CD11b+veCD14+veHLA-DR+veCD163/206+ve M2 TAM), microglia (CD45lowHLD-DR+veCD14+ve), myeloid-derived suppressor cells (MDSC; CD11b+veCD33+veHLA-DRlow/-ve) and regulatory T cells (TREG; CD45+veCD3+veCD4+veCD25+veCD127low/-ve) and the absence of pro-immune cytotoxic effector T cells (CTL; CD45+veCD3+veCD8+ve) (Pimenta et al., 2020; Bikfalvi et al., 2023). The TAM population is also shown to increase in recurrent GBM IME post-irradiation (Tao et al., 2020). However, what leads to the infiltration of tumor suppressive TAMs in primary or recurrent GBM is not known. Therefore, to harness the full potential of immunotherapy and to be able to modulate the TME to immune-stimulating, it's important to understand the molecular mechanisms underlying immunotherapy resistance in GBM, crosstalk between tumor and infiltrating immune cells, and factors that are responsible for TAM infiltration in primary and recurrent GBM. Recently, using cellular and radiation-resistant GBM mouse models, Prof. Shilpee Dutt’s lab demonstrated that post radio-chemotherapy, a small percentage of residual cells survive and have senescent phenotype. Unfortunately, this therapy-induced senescence (TIS) is reversible, leading to recurrence. A very important characteristic of TIS cells is overexpression and secretion of senescence-associated secretory phenotype (SASP), which includes cytokines like IL-1β, IL-6, IL-8, TNF-, (Ketkar et al., 2024). amongst others. Based on these findings, I hypothesize that SASPs secreted by residual senescent cells post radiation treatment are the cause of modulating the GBM tumor microenvironment, making it more immunosuppressive. Thus, this study aims to investigate the contribution and mechanism of radiation-induced senescence in modulating GBM immune microenvironment and TAM enrichment. It also aims to determine the role of NF-κB signalling in mediating this immune crosstalk. Elucidating this relationship is critical for uncovering immune evasion mechanisms and identifying potential therapeutic targets to overcome immunotherapy resistance in GBM.

Glioblastoma, TIS, SASP, NF-κB, immune microenvironment, immunotherapy