Search

International audience; In 2020, the latest French national agricultural censuses show the drastic decline and ageing of the farming population. At the same time, the re-territorialisation of agriculture has been developing, particularly around large cities, with the rise of AMAPs (Association pour le Maintien d'une Agriculture Paysanne in French) for example. In 2014, the French state created a policy to support local farming, farmers’ renewal and local food supply chains: the Territorial Food Projects (TFP), illustrating the rise of the food thematic, at the expense of agriculture in french national and local policies. TFPs aim to adopt a cross-cutting perspective and to integrate urban-rural relationships’ issues. They support territorialized food systems and short food supply chains. They are, first, structured at municipal or regional level, second, based on a shared diagnosis of agriculture and food in the territory between the stakeholders concerned; third on a quality objective in terms of ethics, environment, health, nutrition, etc., and, fourth, on its interconnectedness. This local management allows concerted action between political stakeholders and local food production system actors, thus enable them to produce a coordinated food and agricultural policy at local level. In 2020, local food supply chains have really taken off with the covid-19 pandemic and TFPs have emerged as key policies to meet France's agricultural challenges and fight de-peasantisation. In the framework of the European H2020 project Ruralization, the CNRS team analysed the impact of TFPs on the local development of rural areas. Indeed, this new policy, deeply bottom up and favouring action at the local level, raises questions: what type of agriculture does it encourage? Does it meet farmers' needs? Does it meet the needs of the inhabitants? Does it make food accessible to all? What interactions between urban and rural actors does it promote? And more broadly what kind of local society does it create? Based on several local case studies and reports, the aim of this paper is to understand dynamics and impacts of TFPs on rural regeneration, on farmers’ installation and on agricultural land’s preservation. It aims also to reflect on the limits of this territorial policy and on the evolution of agricultural policies in France.

Immunosuppressive factors, such as soluble major histocompatibility complex class I chain-related peptide A (sMICA) and transforming growth factor beta 1 (TGF-beta1), are involved in tumour immune escape mechanisms (TIEMs) exhibited by head and neck squamous cell carcinomas (HNSCCs) and may represent opportunities for therapeutic intervention. In order to overcome TIEMs, we investigated the antibody-dependent cellular cytotoxicity (ADCC), cytokine release and retargeted tumour-infiltration of sMICA-inhibited patient NK cells expressing Fcγ receptor IIIa (FcγRIIIa, CD16a) in the presence of cetuximab, an anti-EGFR (epidermal growth factor receptor, HER1) monoclonal antibody (mAb). Compared to healthy controls, relapsed HNSCC patients (n = 5) not currently in treatment revealed decreased levels of circulating regulatory NK cell subsets in relation to increased cytotoxic NK cell subpopulations. Elevated sMICA and TGF-beta1 plasma levels correlated with diminished TNFalpha and IFN-gamma release and decreased NKG2D (natural killer group 2 member D)-dependent killing of HNSCC cells by NK cells. Incubation of IL-2-activated patient NK cells with patient plasma containing elevated sMICA or sMICA analogues (shed MICA [shMICA], recombinant MICA [rMICA]) significantly impaired NKG2D-mediated killing by down-regulation of NKG2D surface expression. Of note, CD16 surface expression levels, pro-apoptotic and activation markers, and viability of patient and healthy donor NK cell subpopulations were not affected by this treatment. Accordingly, cetuximab restored killing activity of sMICA-inhibited patient NK cells against cetuximab-coated primary HNSCC cells via ADCC in a dose-dependent manner. Rapid reconstitution of anti-tumour recognition and enhanced tumour-infiltration of treated NK cells was monitored by 24 h co-incubation of HNSCC tumour spheroids with cetuximab (1 µg/ml) and was characterised by increased IFN-gamma and TNFalpha secretion. This data show that the impaired NK cell-dependent tumour-surveillance in relapsed HNSCC patients could be reversed by the re-establishment of ADCC-mediated effector cell activity, thus supporting NK cell-based immunotherapy in combination with antineoplastic monoclonal mAbs.

Disseminated head-and-neck squamous cell carcinoma (HNSCC) escapes immune surveillance and thus frequently manifests as fatal disease. Here, we report on the distribution of distinct immune cell subpopulations, natural killer (NK) cell cytotoxicity and tumor immune escape mechanisms (TIEMs) in 55 HNSCC patients, either at initial diagnosis or present with tumor relapse. Compared to healthy controls, the regulatory NK cells and the ratio of pro/anti-inflammatory cytokines were decreased in HNSCC patients, while soluble major histocompatibility complex Class I chain-related peptide A (sMICA) and transforming growth factor β1 (TGFβ1) plasma levels were markedly elevated. Increased sMICA and TGFβ1 concentrations correlated with tumor progression and staging characteristics in 7 follow-up HNSCC patients, with significantly elevated levels of both soluble factors from the time of initial diagnosis to that of relapse. Patient plasma containing elevated sMICA and TGFβ1 markedly impaired NKG2D-dependent cytotoxicity against HNSCC cells upon incubation with patient-derived and IL-2 activated NK cells vs. those derived from healthy donors. Decreased antitumor recognition was accompanied by reduced NKG2D expression on the NK cell surface and an enhanced caspase-3 activity. In-vitro blocking and neutralization experiments demonstrated a synergistic negative impact of sMICA and TGFβ1 on NK cell functionality. Although we previously showed the feasibility and safety of transfer of allogeneic donor NK cells in a prior clinical study encompassing various leukemia and tumor patients, our present results suggest the need for caution regarding the sole use of adoptive NK cell transfer. The presence of soluble NKG2D ligands in the plasma of HNSCC patients and the decreased NK cell cytotoxicity due to several factors, especially TGFβ1, indicates timely depletion of these immunosuppressing molecules may promote NK cell-based immunotherapy.