Toll-like receptors (TLRs) mediate interactions between environmental stimuli and innate immunity. TLRs play a major role in the development of numerous pancreatic diseases, making these molecules attractive as potential therapeutic targets. TLR2, TLR7 and TLR9 are involved in the initiation of type 1 diabetes mellitus (T1DM), whereas TLR2 and TLR4 play a major role in the onset of type 2 diabetes mellitus (T2DM). Furthermore, TLRs cause derangements in several tumor suppressor proteins (such as p16, p21, p27, p53 and pRb), induce STAT3 activation and promote epithelial-mesenchymal transition as well as oncogene-induced senescence. In this review we will focus on the contribution of TLRs in pancreatic disease including cancer and we describe recent progress in TLR-modulation for the treatment of these patients.

Clear cell Renal Cell Carcinoma (ccRCC) is due to loss of von Hippel–Lindau (VHL) gene and at least one out of three chromatin regulating genes BRCA1-associated protein-1 (BAP1), Polybromo-1 (PBRM1) and Set domain-containing 2 (SETD2). More than 350, 700 and 500 mutations are known respectively for BAP1, PBRM1 and SETD2 genes. Each variation damages these genes with different severity levels. Unfortunately for most of these mutations the molecular effect is unknown, so precluding a severity classification. Moreover, the huge number of these gene mutations does not allow to perform experimental assays for each of them. By bioinformatic tools, we performed predictions of the molecular effects of all mutations lying in BAP1, PBRM1 and SETD2 genes. Our results allow to distinguish whether a mutation alters protein function directly or by splicing pattern destruction and how much severely. This classification could be useful to reveal correlation with patients’ outcome, to guide experiments, to select the variations that are worth to be included in translational/association studies, and to direct gene therapies.

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Colorectal cancer (CRC) represents the second most common cancer in Europe with marked differences in prognosis and response to treatments. In the past years research showed emerging interest in genomic and immunologic fields. The clinical heterogeneity, that occurs during the pathogenesis of CRC, is driven by chromosomal alterations and defective function of DNA mismatch repair genes. CRC is classified in four consensus molecular subtypes (CMS) with different immunogenic characteristics and prognosis. CMS1 microsatellite instable (MSI)-like and CMS4, both characterized by high levels of immune infiltration, are recognized as the most immunogenic subtypes, even though functional characteristic leading to different prognosis are reported. In particular, MSI tumors have been identified as the best candidates for immunotherapy treatment and a number of studies have evaluated the efficacy of anti-programmed cell death ligand-1 (PDL-1) and anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA4) in this setting. However, literature data show that the majority of patients with CRC have microsatellite stable (MSS) tumors and this status seems related to lower response to PDL-1/programmed cell death-1 or CTLA4 blockade. The aim of this paper is to investigate the role of immunotherapy in MSI and MSS CRC.

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