Biology subjects

Chakravarthy, A.

Publications and source records attributed to Chakravarthy, A..

3 recordsLinked to original sources

bioRxiv2018

Pan-cancer deconvolution of cellular composition identifies molecular correlates of antitumour immunity and checkpoint blockade response

The nature and extent of immune cell infiltration into solid tumours are key determinants of therapeutic response. Here, using a novel DNA methylation-based approach to tumour cell fraction deconvolution, we report the integrated analysis of tumour composition and genomics across a wide spectrum of solid cancers. Initially studying head and neck squamous cell carcinoma, we identify two distinct tumour subgroups: immune hot and immune cold, which display differing prognosis, mutation burden, cytokine signalling, cytolytic activity, and oncogenic driver events. We demonstrate the existence of such tumour subgroups pan-cancer, link clonal-neoantigen burden to hot tumours, and show that transcriptional signatures of hot tumours are selectively engaged in immunotherapy responders. We also find that treatment-naive hot tumours are markedly enriched for known immune-resistance genomic alterations and define a catalogue of novel and known mediators of active antitumour immunity, deriving biomarkers and potential targets for precision immunotherapy.

cancer biology↗

bioRxiv2018

Immune evasion and immunotherapy resistance via TGF-beta activation of extracellular matrix genes in cancer associated fibroblasts

The ability to disseminate, invade and successfully colonise other tissues is a critical hallmark of cancer that involves remodelling of the extracellular matrix (ECM) laid down by fibroblasts 1. Moreover, Cancer-Associated-Fibroblasts (CAFs) produce key growth factors and cytokines as components of the ECM that fuel tumour growth, metastasis and chemoresistance, and immune response 2-4. ECM changes also predict prognosis in pancreatic 5 and colorectal cancers 6,7. Here, we examine the landscape of ECM-gene dysregulation pan-cancer and find that a subset of ECM genes is (i) dysregulated specifically in cancer, (ii) adversely prognostic, (iii) linked to TGF-beta signalling and transcription in Cancer-Associated-Fibroblasts, (iv) enriched in immunologically active cancers, and (v) predicts responses to Immune checkpoint blockade better than mutation burden, cytolytic activity, or an interferon signature, thus identifying a novel mechanism of immune evasion for patient stratification in precision immunotherapy and pharmacological modulation.

cancer biology↗

bioRxiv2017

DNA-Demethylating Agents enhance cytolytic activity of CD8+ T Cells and anti-tumor immunity

Recent studies have shown that DNA methyltransferase inhibitors (DNMTi) can induce IRF7 activation and Type I/III interferon signaling through dsRNA-mediated viral mimicry in cancer cells. By performing a large pan-cancer analysis using TCGA data, we determined that IRF7 activation is associated with higher CD8+ T cell tumor infiltration and higher cytolytic activity across multiple cancer types. Accordingly, we demonstrate that DNMTi treatment results in increased CD8+ T cell tumor infiltration, enhanced cytolytic activity and CD8+ T cell dependent tumor growth inhibition. Finally, we show that DNMTi triggers a process marked by the induction of viral mimicry directly on CD8+ T cells, leading to activation of dsRNA sensing pathway, and up-regulation of T cell activation markers, effector cytokines, and Granzyme B. Taken together, our findings suggest that dsRNA sensing pathway activation in the immune compartment, through pharmacological DNA demethylation, is a viable strategy for boosting anti-tumor immune response.

cancer biology↗