Pan-cancer deconvolution of tumour composition using DNA methylation

The nature and extent of immune cell infiltration into solid tumours are key determinants of therapeutic response. Here, using a 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 cytotoxic T-lymphocyte infiltration, 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, potentially explaining the heterogeneity of immunotherapy response and prognosis seen within this group. Finally, we define a catalogue of mediators of active antitumour immunity, deriving candidate biomarkers and potential targets for precision immunotherapy

The intratumoural subsite and relation of CD8(+) and FOXP3(+) T lymphocytes in colorectal cancer provide important prognostic clues

Background: To find improved tools for prognostic evaluation in patients with colorectal cancer (CRC), we have analysed how infiltration of cytotoxic T lymphocytes (CD8(+)) and regulatory T lymphocytes (FoxP3(+)) correlates to prognosis, not only according to quantity and relation, but also to subsite within tumours of different molecular characteristics (microsatellite instability and CpG island methylator phenotype status). Methods: CD8 and FOXP3 expression was evaluated by immunohistochemistry in 426 archival tumour tissue samples from patients surgically resected for CRC. The average infiltration of CD8(+) and FOXP3(+) cells was assessed along the tumour invasive front, in the tumour centre and within the tumour epithelium (intraepithelial). Results: We found that infiltration of CD8(+) T lymphocytes within the tumour epithelium provided the strongest prognostic information (P < 0.001). At the tumour invasive front and tumour centre, FOXP3 expression withheld the strongest association to prognosis (P < 0.001), suggesting FOXP3(+) T-lymphocyte infiltration to be a better prognostic tool than CD8(+) T lymphocytes at these intratumoural subsites. We further analysed the possible prognostic impact of the relation between these T-cell subsets, finding that a high intraepithelial CD8 expression was associated with a better patient outcome, independent of FOXP3 infiltration. In groups of low intraepithelial CD8 expression, however, a high infiltration rate of FOXP3(+) cells at the tumour invasive front, significantly improved prognosis. Conclusions: Analyses of intraepithelial infiltration of CD8(+) T lymphocytes, infiltration of FOXP3(+) T lymphocytes at the tumour front or centre, and the relation between these subsets, may be a valuable tool for predicting prognosis in colon cancer

Immunotherapy with checkpoint inhibitors in patients with ovarian cancer: Still promising?

Despite advances in surgery and chemotherapy and the integration of antivascular endothelial growth factor therapy as well as poly(adenosine diphosphate–ribose) polymerase inhibitors into daily clinical practice, epithelial ovarian cancer remains the leading cause of death from gynecological cancer. The incorporation of new therapies with the potential to achieve long-term disease remission is a clear need for patients with ovarian cancer. Immunotherapy with checkpoint inhibitors (CPIs) (antiprogrammed cell death protein 1 [anti-PD-1] or antiprogrammed death-ligand 1 [anti-PD-L1]) has been adopted in several malignancies based on improvements shown with regard to progression-free survival and in particular overall survival. Although there is a solid rationale for the use of CPIs in patients with ovarian cancer, to our knowledge the clinical data presented to date are not very convincing. This article reviews the current data regarding CPIs in patients with ovarian cancer along with the future directions and designs of clinical trials aiming to overcome the low efficacy of CPIs in these individuals