Celiac disease: how complicated can it get?

In the small intestine of celiac disease patients, dietary wheat gluten and similar proteins in barley and rye trigger an inflammatory response. While strict adherence to a gluten-free diet induces full recovery in most patients, a small percentage of patients fail to recover. In a subset of these refractory celiac disease patients, an (aberrant) oligoclonal intraepithelial lymphocyte population develops into overt lymphoma. Celiac disease is strongly associated with HLA-DQ2 and/or HLA-DQ8, as both genotypes predispose for disease development. This association can be explained by the fact that gluten peptides can be presented in HLA-DQ2 and HLA-DQ8 molecules on antigen presenting cells. Gluten-specific CD4+ T cells in the lamina propria respond to these peptides, and this likely enhances cytotoxicity of intraepithelial lymphocytes against the intestinal epithelium. We propose a threshold model for the development of celiac disease, in which the efficiency of gluten presentation to CD4+ T cells determines the likelihood of developing celiac disease and its complications. Key factors that influence the efficiency of gluten presentation include: (1) the level of gluten intake, (2) the enzyme tissue transglutaminase 2 which modifies gluten into high affinity binding peptides for HLA-DQ2 and HLA-DQ8, (3) the HLA-DQ type, as HLA-DQ2 binds a wider range of gluten peptides than HLA-DQ8, (4) the gene dose of HLA-DQ2 and HLA-DQ8, and finally,(5) additional genetic polymorphisms that may influence T cell reactivity. This threshold model might also help to understand the development of refractory celiac disease and lymphoma

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

Genomic Analyses Reveal Global Functional Alterations That Promote Tumor Growth and Novel Tumor Suppressor Genes in Natural Killer-Cell Malignancies

50th Annual Meeting of the American-Society-of-Hematology, San Francisco, CA, 06-09 December 2008. In Blood, v. 112 n. 11, p. 129

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