Over the past decade, metabolic reprogramming has been defined as a hallmark of cancer. More recently, a large number of studies have demonstrated that metabolic reprogramming can modulate the ...differentiation and functions of immune cells, and thus modify the antitumor response. Increasing evidence suggests that modified energy metabolism could be responsible for the failure of antitumor immunity. Indeed, tumor-infiltrating immune cells play a key role in cancer, and metabolic switching in these cells has been shown to help determine their phenotype: tumor suppressive or immune suppressive. Recent studies in the field of immunometabolism focus on metabolic reprogramming in the tumor microenvironment (TME) by targeting innate and adaptive immune cells and their associated anti- or protumor phenotypes. In this review, we discuss the lipid metabolism of immune cells in the TME as well as the effects of lipids; finally, we expose the link between therapies and lipid metabolism.
CXCR6 is a receptor for the chemokine CXCL16, which exists as a membrane or soluble form. CXCR6 is a marker for resident memory T (T
RM
) cells that plays a role in immunosurveillance through their ...interaction with epithelial cells. The interaction of CXCR6 with CXCL16 expressed at the membrane of certain subpopulations of intratumor dendritic cells (DC) called DC3, ideally positions these CXCR6
+
T cells to receive a proliferation signal from IL-15 also presented by DC3. Mice deficient in
cxcr6
or blocking the interaction of CXCR6 with its ligand, experience a poorer control of tumor proliferation by CD8
+
T cells, but also by NKT cells especially in the liver. Intranasal vaccination induces CXCL16 production in the lungs and is associated with infiltration by T
RM
expressing CXCR6, which are then required for the efficacy of anti-tumor vaccination. Therapeutically, the addition of CXCR6 to specific CAR-T cells enhances their intratumoral accumulation and prolongs survival in animal models of pancreatic, ovarian and lung cancer. Finally, CXCR6 is part of immunological signatures that predict response to immunotherapy based on anti-PD-(L)1 in various cancers. In contrast, a protumoral role of CXCR6
+
T cells has also been reported mainly in Non-alcoholic steatohepatitis (NASH) due to a non-antigen specific mechanism. The targeting and amplification of antigen-specific T
RM
expressing CXCR6 and its potential use as a biomarker of response to immunotherapy opens new perspectives in cancer treatment.
The structural properties, relative stabilities, electronic, and thermodynamic properties, of Li+Nen (n = 1-20) clusters have been studied based on a pairwise model and density functional theory ...(DFT) methods. In the pairwise method, the potential energy surface considered interactions between Li+Ne, Ne - Ne, and many-body term. For the DFT calculations, the B3LYP functional combined with the 6-311 + + G (2d,2p) basis sets has been employed. In both methods, the Li+Ne6 cluster demonstrated high stability with an octahedral structure, where the Li+ cation was surrounded by Ne atoms. Thus, the octahedral Li+Ne6 structure was considered to be the core for larger cluster sizes. Relative stabilities were assessed based on binding energies, second-order differences of energies, transition dipole moment, and HOMO-LUMO energy gaps. Furthermore, thermodynamic properties were calculated, revealing that the formation process of Li+Nen clusters is endothermic and nonspontaneous.
Cellular senescence is a cell state involved in both physiological and pathological processes such as age-related diseases and cancer. While the mechanism of senescence is now well known, its role in ...tumorigenesis still remains very controversial. The positive and negative effects of senescence on tumorigenesis depend largely on the diversity of the senescent phenotypes and, more precisely, on the senescence-associated secretory phenotype (SASP). In this review, we discuss the modulatory effect of nitric oxide (NO) in SASP and the possible benefits of the use of NO donors or iNOS inducers in combination with senotherapy in cancer treatment.
Immunotherapy has allowed major advances in oncology in the past years, in particular with the development of immune checkpoint inhibitors, but the clinical benefits are still limited, particularly ...in colorectal cancer (CRC). Our scientific approach is based on the search for innovative immunotherapy with a final goal that aims to induce an effective antitumor immune response in CRC. Here, we focused on a multikinase inhibitor, H89. We carried out
experiments based on syngeneic mouse models of colon cancer in BALB/c mice and chemically colon tumorigenesis. Flow cytometry, RNAseq, RT-qPCR, antibody-specific immune cell depletion, and Western blot were used to identify the immune cell type involved in the preventive and antitumor activity of H89. We demonstrated that H89 delays colon oncogenesis and prevents tumor growth. This latter effect seems to involve NK cells. H89 also inhibits colon tumor growth in a T-cell-dependent manner. Analysis of the immune landscape in the tumor microenvironment showed an increase of CD4
Th1 cells and CD8
cytotoxic T cells but a decrease of CD4
T
cell infiltration. Mechanistically, we showed that H89 could promote naïve CD4
T-cell differentiation into Th1, a decrease in T
differentiation, and an increase in CD8
T-cell activation and cytotoxicity
. Furthermore, H89 induced overexpression of genes involved in antitumor immune response, such as IL-15RA, which depletion counteracts the antitumor effect of H89. We also found that H89 regulated Akt/PP2A pathway axis, involved in TCR and IL-15 signaling transduction. Our findings identify the H89 as a potential strategy for immune system activation leading to the prevention and treatment of CRC.
(1) Background: Immunosuppression is a key barrier to effective anti-cancer therapies, particularly in triple-negative breast cancer (TNBC), an aggressive and difficult to treat form of breast ...cancer. We investigated here whether the combination of doxorubicin, a standard chemotherapy in TNBC with glyceryltrinitrate (GTN), a nitric oxide (NO) donor, could overcome chemotherapy resistance and highlight the mechanisms involved in a mouse model of TNBC. (2) Methods: Balb/C-bearing subcutaneous 4T1 (TNBC) tumors were treated with doxorubicin (8 mg/Kg) and GTN (5 mg/kg) and monitored for tumor growth and tumor-infiltrating immune cells. The effect of treatments on MDSCs reprogramming was investigated ex vivo and in vitro. (3) Results: GTN improved the anti-tumor efficacy of doxorubicin in TNBC tumors. This combination increases the intra-tumor recruitment and activation of CD8
lymphocytes and dampens the immunosuppressive function of PMN-MDSCs PD-L1
. Mechanistically, in PMN-MDSC, the doxorubicin/GTN combination reduced STAT5 phosphorylation, while GTN +/- doxorubicin induced a ROS-dependent cleavage of STAT5 associated with a decrease in FATP2. (4) Conclusion: We have identified a new combination enhancing the immune-mediated anticancer therapy in a TNBC mouse model through the reprograming of PMN-MDSCs towards a less immunosuppressive phenotype. These findings prompt the testing of GTN combined with chemotherapies as an adjuvant in TNBC patients experiencing treatment failure.
Many molecular targets for cancer therapy are located in the cytosol. Therapeutic macromolecules are generally not able to spontaneously translocate across membranes to reach these cytosolic targets. ...Therefore a strong need exists for tools that enhance cytosolic delivery. Shiga toxin B-subunit (STxB) is used to deliver therapeutic principles to disease-relevant cells that express its receptor, the glycolipid Gb3. Based on its naturally existing membrane translocation capacity, STxB delivers antigens to the cytosol of Gb3-positive dendritic cells, leading to the induction of CD8
T cells. Here, we have explored the possibility of further increasing the membrane translocation of STxB to enable other therapeutic applications. For this, our capacity to synthesize STxB chemically was exploited to introduce unnatural amino acids at different positions of the protein. These were then functionalized with hydrophobic entities to locally destabilize endosomal membranes. Intracellular trafficking of these functionalized STxB was measured by confocal microscopy and their cytosolic arrival with a recently developed highly robust, sensitive, and quantitative translocation assay. From different types of hydrophobic moieties that were linked to STxB, the most efficient configuration was determined. STxB translocation was increased by a factor of 2.5, paving the path for new biomedical opportunities.
We report a computational study of the potential energy surface (PES) and vibrational bound states for the ground electronic state of Li2+Kr. The PES was calculated in Jacobi coordinates at the ...Restricted Coupled Cluster method RCCSD(T) level of calculation and using aug-cc-pVnZ (
= 4 and 5) basis sets. Afterward, this PES is extrapolated to the complete basis set (CBS) limit for correction. The obtained interaction energies were, then, interpolated numerically using the reproducing kernel Hilbert space polynomial (RKHS) approach to produce analytic expressions for the 2D-PES. The analytical PES is used to solve the nuclear Schrodinger equation to determine the bound states' eigenvalues of Li2+Kr for a J = 0 total angular momentum configuration and to understand the effects of orientational anisotropy of the forces and the interplay between the repulsive and attractive interaction within the potential surface. In addition, the radial and angular distributions of some selected bound state levels, which lie below, around, and above the T-shaped 90° barrier well, are calculated and discussed. We note that the radial distributions clearly acquire a more complicated nodal structure and correspond to bending and stretching vibrational motions "mode" of the Kr atom along the radial coordinate, and the situation becomes very different at the highest bound states levels with energies higher than the T-shaped 90° barrier well. The shape of the distributions becomes even more complicated, with extended angular distributions and prominent differences between even and odd states.
We report a computational study of the potential energy surface (PES) and vibrational bound states for the ground electronic state of Lisub.2 sup.+Kr. The PES was calculated in Jacobi coordinates at ...the Restricted Coupled Cluster method RCCSD(T) level of calculation and using aug-cc-pVnZ (n = 4 and 5) basis sets. Afterward, this PES is extrapolated to the complete basis set (CBS) limit for correction. The obtained interaction energies were, then, interpolated numerically using the reproducing kernel Hilbert space polynomial (RKHS) approach to produce analytic expressions for the 2D-PES. The analytical PES is used to solve the nuclear Schrodinger equation to determine the bound states’ eigenvalues of Lisub.2 sup.+Kr for a J= 0 total angular momentum configuration and to understand the effects of orientational anisotropy of the forces and the interplay between the repulsive and attractive interaction within the potential surface. In addition, the radial and angular distributions of some selected bound state levels, which lie below, around, and above the T-shaped 90° barrier well, are calculated and discussed. We note that the radial distributions clearly acquire a more complicated nodal structure and correspond to bending and stretching vibrational motions “mode” of the Kr atom along the radial coordinate, and the situation becomes very different at the highest bound states levels with energies higher than the T-shaped 90° barrier well. The shape of the distributions becomes even more complicated, with extended angular distributions and prominent differences between even and odd states.
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