Beyond the concept of cold and hot tumors for the development of novel predictive biomarkers and the rational design of immunotherapy combination.

Immunotherapy has revolutionized the management of cancers. At the end of 2018, 1,716 clinical trials assessed regimen that combine program death-1 (PD-1)/program death ligand-1 (PD-L1) blockers with other cancer therapies (tyrosine kinase inhibitor, chemotherapy and radiotherapy). There is a contrast between these clinical dynamics and the difficulty of identifying biomarkers to better select patients that could benefit from immunotherapy. In this context, different tumor classifications have been proposed to try to better stratify patients. They rely on the characteristics of the tumor microenvironment and led first to divide them into hot and cold tumors. In this review, we aim to demonstrate the limitations of this classification focusing on the differential significance of subpopulations of intratumor CD8 + T cells. We also underline novel mechanisms of resistance to anti-PD-1/PD-L1 blockade, focusing on myeloid cells, hypoxia and tumor immunoediting under treatment. Understanding the mechanisms of resistance to immune-checkpoint inhibitor is indeed a powerful research driver that allows further identification of novel biomarkers, drug development and bring a rational to innovative therapeutic combinations.

Inhibition of the differentiation of monocyte-derived dendritic cells by human gingival fibroblasts.

We investigated whether gingival fibroblasts (GFs) can modulate the differentiation and/or maturation of monocyte-derived dendritic cells (DCs) and analyzed soluble factors that may be involved in this immune modulation. Experiments were performed using human monocytes in co-culture with human GFs in Transwell® chambers or using monocyte cultures treated with conditioned media (CM) from GFs of four donors. The four CM and supernatants from cell culture were assayed by ELISA for cytokines involved in the differentiation of dendritic cells, such as IL-6, VEGF, TGFß1, IL-13 and IL-10. The maturation of monocyte-derived DCs induced by LPS in presence of CM was also studied. Cell surface phenotype markers were analyzed by flow cytometry. In co-cultures, GFs inhibited the differentiation of monocyte-derived DCs and the strength of this blockade correlated with the GF/monocyte ratio. Conditioned media from GFs showed similar effects, suggesting the involvement of soluble factors produced by GFs. This inhibition was associated with a lower stimulatory activity in MLR of DCs generated with GFs or its CM. Neutralizing antibodies against IL-6 and VEGF significantly (P<0.05) inhibited the inhibitory effect of CM on the differentiation of monocytes-derived DCs and in a dose dependent manner. Our data suggest that IL-6 is the main factor responsible for the inhibition of DCs differentiation mediated by GFs but that VEGF is also involved and constitutes an additional mechanism.

Impact of photodynamic therapy on inflammatory cells during human chronic periodontitis.

The aim of this study was to evaluate the effects of the photodynamic therapy (PDT) on the inflammatory infiltrate and on the collagen network organization in human advanced chronic periodontitis. Two different drug delivery systems (DDS) were tested (liposomes and nanoemulsions) to determine if the effects of PDT could differ according to the DDS used. Sixteen patients presenting two teeth with chronic advanced periodontitis and important tooth mobility with clinical indication of extraction were included in the group liposomes (group L, n=8) or in the group nanoemulsions (group N, n=8) in order to compare the effects of each DDS. Seven days before extractions one tooth of each patient was treated with PDT using phthalocyanine derivatives as photosensitizers and the contralateral tooth was taken as control. In group L the density of gingival collagen fibers (66±19%) was significantly increased (p<0.02) when compared to controls (35±21%). Concerning the antigen-presenting cells, PDT had differential effects depending on the drug delivery system; the number of macrophages was significantly decreased (p<0.05) in group L while the number of Langerhans cells was significantly decreased in group N (p<0.02). These findings demonstrate that PDT presents an impact on gingival inflammatory phenomenon during chronic periodontitis and leads to a specific decrease of antigen-presenting cells populations according to the drug delivery system used.

Fusiform aneurysm model in rabbit carotid artery.

AIMS: To develop a reproducible and accessible model of elastase-induced fusiform aneurysm in carotid rabbit arteries. METHODS: Elastase, at a concentration of 1-30 U, was incubated into the lumen of carotid rabbit arteries. Four weeks later, angiography, histomorphometry, immunohistochemistry and zymography were performed. RESULTS: The optimal concentration of elastase in this model was 3 U according to the balance between mortality and thrombosis rates. Indeed, at 3 U, external carotid diameter increased from 1.9 +/- 0.1 to 3.1 +/- 0.4 mm (p < 0.0001) associated with degradation of elastic fibers, matrix metalloproteinase-9 secretion, apoptosis and macrophage infiltration. CONCLUSIONS: Our study underlines that abdominal aortic aneurysm can be reliably duplicated in an elastase-induced aneurysm in carotid artery, a much more accessible vessel.

Tissular senescence and modifications of oral ecosystem in the elderly: risk factors for mucosal pathologies.

The aim of this present review is to describe the pathogenesis and mechanisms behind mucosal pathologies in the elderly including a description of the risk factors for these pathologies. The oral cavity - and particularly oral mucosae - is exposed to many stresses as well as physical, chemical, thermic and pathogenic agents. In the elderly, mucosae are less resistant to the insults, and this increases the occurrence of diseases. Several factors contribute to the prevalence of mucosal pathologies with aging. There are two categories: intrinsic factors linked to the senescence of the tissues and functions, and extrinsic factors related to the older people general health status. The intrinsic factors are: 1) mucosal senescence which induces fragility 2) immunosenescence which causes a decrease in the host response against micro-organisms and an increase in the autoimmune diseases and 3) senescence of salivary glands and reduction of the saliva protective function. Furthermore, there are extrinsic factors which contribute to change the oral ecosystem during aging, such as polypathologies and polymedications, malnutrition, degradation of oral hygiene, pathogen proliferation (mainly bacteria and Candida species) and old or ill-fitted removable dentures. In the elderly several diseases occur on the oral mucosae: inflammation, bacterial infections or candidiasis, ulcerations, autoimmune dermatosis, tumoral processes. This review describes some common oral mucosal pathologies in the older people, which illustrate the impact of different risk factors described in the first part.