Biology subjects

Nambiar, D. K.

Publications and source records attributed to Nambiar, D. K..

3 recordsLinked to original sources

bioRxiv2023

Innate immune receptor C5aR1 regulates cancer cell fate and can be targeted to improve radiotherapy in tumours with immunosuppressive microenvironments

An immunosuppressive microenvironment causes poor tumour T-cell infiltration and is associated with reduced patient overall survival in colorectal cancer. How to improve treatment responses in these tumours is still a challenge. Using an integrated screening approach to identify cancer-specific vulnerabilities, we identify complement receptor C5aR1 as a druggable target which when inhibited improves radiotherapy even in tumours displaying immunosuppressive features and poor CD8+ T-cell infiltration. While C5aR1 is well-known for its role in the immune compartment, we find that C5aR1 is also robustly expressed on malignant epithelial cells, highlighting potential tumour-cell specific functions. C5aR1 targeting results in increased NF-{kappa}B-dependent apoptosis specifically in tumours and not normal tissues; indicating that in malignant cells, C5aR1 primarily regulates cell fate. Collectively, these data reveal that increased complement gene expression is part of the stress response mounted by irradiated tumours and that targeting C5aR1 can improve radiotherapy even in tumours displaying immunosuppressive features.

cancer biology↗

bioRxiv2021

Aldehyde dehydrogenase 3A1 deficiency leads to mitochondrial dysfunction and impacts salivary gland stem cell self-renewal, differentiation and survival

Adult salivary stem/progenitor cells (SSPC) have an intrinsic property to self-renew in order to maintain tissue architecture and homeostasis. Adult salivary glands have been documented to harbor SSPC, which have been shown to play a vital role in the regeneration of the glandular structures post radiation damage. We have previously demonstrated that activation of aldehyde dehydrogenase 3A1 (ALDH3A1) after radiation reduced aldehyde accumulation in SSPC, leading to less apoptosis and improved salivary function. We subsequently found that sustained pharmacological ALDH3A1 activation is critical to enhance regeneration of murine submandibular gland after radiation damage. Further investigation shows that ALDH3A1 function is crucial for SSPC self-renewal and differentiation even in the absence of radiation stress. Salivary glands from Aldh3a1-null mice have fewer acinar structures than wildtype mice. ALDH3A1 deletion or pharmacological inhibition in SSPC leads to a decrease in mitochondrial DNA copy number, lower expression of mitochondrial specific genes and proteins, structural abnormalities, lower membrane potential, and reduced cellular respiration. Loss or inhibition of ALDH3A1 also elevates ROS levels and accumulation of ALDH3A1 substrate 4-hydroxynonenal (4-HNE, a lipid peroxidation product), leading to decreased survival of murine SSPC that can be rescued by treatment with 4-HNE specific carbonyl scavengers. Our data indicate that ALDH3A1 activity protects mitochondrial function and is important for the development and regeneration activity of SSPC. This knowledge will help to guide our translational strategy of applying ALDH3A1 activators in the clinic to prevent radiation-related hyposalivation in head and neck cancer patients.

cell biology↗

bioRxiv2020

Targeting C5aR1 Increases the Therapeutic Window of Radiotherapy

Engaging innate immune pathways is emerging as a productive way of achieving durable anti-tumor responses. However, systemic administration of these therapies can result in toxicity, deemed to be particularly problematic when combined with current standard-of-care cytotoxic treatments such as radiotherapy. Increasing the therapeutic window of radiotherapy may be achieved by using targeted therapies, however, few pre-clinical studies investigate both tumor and normal tissue responses in detail. Here we show that targeting innate immune receptor C5aR1 improves tumor radiation response while reducing radiation-induced normal tissue toxicity, thereby increasing the therapeutic window. Genetically or pharmacologically targeting C5aR1 increases both IL-10 expression in the small intestine and IL-10 secretion by tumor cells. Increased IL-10 attenuates RelA phosphorylation and increases apoptosis in tumor cells, leading to improved radiation responses in murine models. Of note, these radiosensitizing effects are tumor-specific since, in the gastrointestinal tract, targeting C5aR1 instead results in decreased crypt cell apoptosis reduced signs of histological damage and improved survival following total abdominal irradiation in mice. Furthermore, the potent and orally active C5aR1 inhibitor, PMX205, improves tumor radiation responses even in a context of reduced/absent CD8+ T cell infiltration. These data indicate that PMX205 can modulate cancer-cell intrinsic functions to potentiate anti-tumor radiation responses even in tumors displaying features of T-cell deficiency or exclusion. Finally, using a preclinical murine model allowing the simultaneous assessment of tumor and normal tissue radiation responses, we show that PMX205 treatment reduces histological and functional markers of small-bowel toxicity while affording a positive tumor response. Our data, therefore, suggest that targeting C5aR1 could be a promising approach for increasing the therapeutic window of radiotherapy.

cancer biology↗