Mitochondrial metabolism sustains CD8+ T cell migration for an efficient infiltration into solid tumors.

The ability of CD8+ T cells to infiltrate solid tumors and reach cancer cells is associated with improved patient survival and responses to immunotherapy. Thus, identifying the factors controlling T cell migration in tumors is critical, so that strategies to intervene on these targets can be developed. Although interstitial motility is a highly energy-demanding process, the metabolic requirements of CD8+ T cells migrating in a 3D environment remain unclear. Here, we demonstrate that the tricarboxylic acid (TCA) cycle is the main metabolic pathway sustaining human CD8+ T cell motility in 3D collagen gels and tumor slices while glycolysis plays a more minor role. Using pharmacological and genetic approaches, we report that CD8+ T cell migration depends on the mitochondrial oxidation of glucose and glutamine, but not fatty acids, and both ATP and ROS produced by mitochondria are required for T cells to migrate. Pharmacological interventions to increase mitochondrial activity improve CD8+ T cell intratumoral migration and CAR T cell recruitment into tumor islets leading to better control of tumor growth in human xenograft models. Our study highlights the rationale of targeting mitochondrial metabolism to enhance the migration and antitumor efficacy of CAR T cells in treating solid tumors.

Designing a high-yielding maize ideotype for a changing climate in Lombardy plain (northern Italy).

The expected climate change will affect the maize yields in view of air temperature increase and scarce water availability. The application of biophysical models offers the chance to design a drought-resistant ideotype and to assist plant breeders and agronomists in the assessment of its suitability in future scenarios. The aim of the present work was to perform a model-based estimation of the yields of two hybrids, current vs ideotype, under future climate scenarios (2030-2060 and 2070-2100) in Lombardy (northern Italy), testing two options of irrigation (small amount at fixed dates vs optimal water supply), nitrogen (N) fertilization (300 vs 400 kg N ha(-1)), and crop cycle durations (current vs extended). For the designing of the ideotype we set several parameters of the ARMOSA process-based crop model: the root elongation rate and maximum depth, stomatal resistance, four stage-specific crop coefficients for the actual transpiration estimation, and drought tolerance factor. The work findings indicated that the current hybrid ensures good production only with high irrigation amount (245-565 mm y(-1)). With respect to the current hybrid, the ideotype will require less irrigation water (-13%, p<0.01) and it resulted in significantly higher yield under water stress condition (+15%, p<0.01) and optimal water supply (+2%, p<0.05). The elongated cycle has a positive effect on yield under any combination of options. Moreover, higher yields projected for the ideotype implicate more crop residues to be incorporated into the soil, which are positively correlated with the SOC sequestration and negatively with N leaching. The crop N uptake is expected to be adequate in view of higher rate of soil mineralization; the N fertilization rate of 400 kg N ha(-1) will involve significant increasing of grain yield, and it is expected to involve a higher rate of SOC sequestration.

Modelling nitrogen leaching from sewage sludge application to arable land in the Lombardy region (northern Italy).

Sewage sludge can be used as fertiliser, offering the possibility of safely recycling this waste product as a resource in agricultural applications. As the environmental concerns related to waste recycling in agricultural applications are well-known, restrictions on the use of sewage sludge have been implemented by the EU and local authorities. This work aimed to evaluate the nitrogen leaching associated with the application of sludge and the effectiveness of the temporal restrictions on its application implemented to safeguard the environment in the Lombardy region of northern Italy (120 days in Nitrate Vulnerable Zones and 90 days elsewhere) using the CropSyst model which was first validated. The effects of fertilisation using four different sludge types on N leaching were simulated at five sites under cultivation with maize and rice crops; six different timing schemes for sludge application were tested, three of which involved dates that were in agreement (AT) with the regulation, while the other three were not in agreement (NAT). We detected a significant effect of the sludge type and application timing, whereas the effect of their interaction was never significant. The mean annual leaching was 22 to 154 kg N ha(-1). The higher the ammonium N content in the sludge was, the greater the potential for N leaching was found to be. For the maize crop, the distribution of sludge in the late fall period resulted in significantly greater N leaching (61 kg N ha(-1)) and led to lower yields (9 t DM ha(-1)) compared to late winter fertilisation (49 kg N ha(-1); 10 t DM ha(-1)), whereas no differences in N leaching or yield were detected between AT and NAT, which was also observed for the rice crop. Therefore, the applied temporal constraints did not always appear to be advantageous for protecting the environment from leaching.