Biology subjects

Illidge, T.

Publications and source records attributed to Illidge, T..

3 recordsLinked to original sources

bioRxiv2026

In situ programming of intratumoural stem cell-like memory CD8+ T cells enables durable antitumour immunity in immunosuppressive tumours

Tumours with an immunosuppressive microenvironment often respond poorly to radiotherapy (RT) and immune checkpoint inhibitors, and durable clinical responses remain rare. These failures are not solely explained by insufficient immune activation, but instead reflect an inability of current therapies to establish CD8 T-cell infiltration and states required for long-term tumour control. Although stem cell-like memory CD8 T cells (Tscm) are critical for durable antitumour immunity, they are typically rare within solid tumours, and strategies to selectively augment the expansion of intratumoural Tscm within immunosuppressive tumours are lacking. Here, we show that intratumoural immune modulation via pattern recognition receptor (PRR) activation, using a double-stranded RNA-based agonist (BO-112), promotes Tscm expansion and, in combination with radiation, enhances antitumour immunity in poorly immunogenic lung and bladder cancer models. PRR activation enabled selective in situ expansion of intratumoural Tscm, rather than global CD8 T-cell activation. Therapeutic efficacy required pre-existing intratumoural CD8 T cells and was associated with qualitative reprogramming of the immune landscape, including depletion of exhausted CD8 T cells and regulatory T cells. Transcriptomic analyses showed that PRR activation preferentially enriched programmes associated with Tscm formation and self-renewal, whereas durable effector differentiation emerged only following combined RT-PRR agonist treatment, consistent with antigen-driven execution of the expanded progenitor pool. A Tscm-associated gene signature derived from these preclinical datasets correlated with improved survival across independent human lung and bladder cancer cohorts. Together, our data identify intratumoural Tscm as a therapeutically targetable immune-control axis and establish in situ programming of Tscm as a route to durable antitumour immunity.

cancer biology↗

bioRxiv2022

IRF7 impacts on prostate cancer cell survival in response to radiation

Understanding the impact of radiotherapy on the evolution of treatment resistant prostate cancer is critical for selecting effective treatment combinations. Whilst activation of Type 1 interferon signalling is a hallmark of how cells respond to viral infection, in cancer cells, multiple stresses are known to activate this same response. In this study we have evaluated for the first time the changes in the interferon response induced by culturing prostate cancer cells under sphere- forming conditions and following irradiation. We report a conserved upregulated transcript profile for both conditions that is strongly associated with therapeutic resistance and cell survival in vitro and in vivo. The profile includes and is regulated by the Type 1 interferon master regulator IRF7 which, when depleted, delays tumour re-growth following irradiation. We immuno-stained two independent prostate cohorts for IRF7 and found that increased expression, particularly in cases with low PTEN expression, correlated with poor prognosis. To more comprehensively characterise the impact of IRF7 and radiation on cells, RNA-Seq was performed on IRF7 knockdown cells at different radiation doses. We identified a number of biological processes that were IRF7-dependent, including the formation of stem-like cell populations and also therapeutic vulnerabilities. For example, irradiation sensitised surviving cells to either a combination of an IKK{varepsilon}/TBK1 and a MEK inhibitor or treatment with an inhibitor of IDO1, an IRF7- dependent gene. Translationally our work suggests that IRF7 expression can be used to stratify patients who may not benefit from receiving radiotherapy alone but rather may benefit from treatment combinations. In two cohorts treated with radical intent, strong IRF7 staining was associated with disease-specific death implicating this pathway as a convergence point for therapeutic resistance in prostate and potentially other cancer types.

cancer biology↗

bioRxiv2020

Development of a novel allograft model of prostate cancer: a new tool to inform clinical translation

BackgroundAllograft models enable characterisation of genomic drivers and treatment responses by modelling immune and micro-environmental changes more accurately than xenografts. Despite this, few models are available to the prostate cancer (PCa) community. This study presents a novel allograft model of high-risk, localised PCa. In characterising this model we have focused on its response to radiotherapy (RT). MethodsThe DVL3 cell line was derived from a transgenic trp53-/-/Pten-/- mouse model and characterised both in vitro and in vivo. The DVL3 cells were allografted and response to RT was investigated and compared to the TRAMP-C1 model. Extensive tumour profiling in the DVL3 model was performed using flow cytometry, immunohistochemistry and RNA-seq. ResultsIn vitro the DVL3 cells expressed basal and luminal markers. DVL3 cells formed tumours with distinct glandular morphology which expressed androgen receptor, similar to human localised PC. DVL3 tumour growth was delayed following administration of fractionated RT, with infiltration of myeloid derived suppressor cells (MDSC). ConclusionsThe DVL3 allograft model represents substantial progress in PCa modelling, displaying; luminal differentiation, strong AR expression, and an immunosuppressive microenvironment, similar to observations in high-risk PCa patients. This model is ideally suited for development and validation of novel therapeutics, in particular immune-modulatory agents in combination with RT.

cancer biology↗