TCR-independent CD137 (4-1BB) signaling promotes CD8+-exhausted T cell proliferation and terminal differentiation.

CD137 (4-1BB)-activating receptor represents a promising cancer immunotherapeutic target. Yet, the cellular program driven by CD137 and its role in cancer immune surveillance remain unresolved. Using T cell-specific deletion and agonist antibodies, we found that CD137 modulates tumor infiltration of CD8+-exhausted T (Tex) cells expressing PD1, Lag-3, and Tim-3 inhibitory receptors. T cell-intrinsic, TCR-independent CD137 signaling stimulated the proliferation and the terminal differentiation of Tex precursor cells through a mechanism involving the RelA and cRel canonical NF-κB subunits and Tox-dependent chromatin remodeling. While Tex cell accumulation induced by prophylactic CD137 agonists favored tumor growth, anti-PD1 efficacy was improved with subsequent CD137 stimulation in pre-clinical mouse models. Better understanding of T cell exhaustion has crucial implications for the treatment of cancer and infectious diseases. Our results identify CD137 as a critical regulator of Tex cell expansion and differentiation that holds potential for broad therapeutic applications.

Eomes-Dependent Loss of the Co-activating Receptor CD226 Restrains CD8+ T Cell Anti-tumor Functions and Limits the Efficacy of Cancer Immunotherapy.

CD8+ T cells within the tumor microenvironment (TME) are exposed to various signals that ultimately determine functional outcomes. Here, we examined the role of the co-activating receptor CD226 (DNAM-1) in CD8+ T cell function. The absence of CD226 expression identified a subset of dysfunctional CD8+ T cells present in peripheral blood of healthy individuals. These cells exhibited reduced LFA-1 activation, altered TCR signaling, and a distinct transcriptomic program upon stimulation. CD226neg CD8+ T cells accumulated in human and mouse tumors of diverse origin through an antigen-specific mechanism involving the transcriptional regulator Eomesodermin (Eomes). Despite similar expression of co-inhibitory receptors, CD8+ tumor-infiltrating lymphocyte failed to respond to anti-PD-1 in the absence of CD226. Immune checkpoint blockade efficacy was hampered in Cd226-/- mice. Anti-CD137 (4-1BB) agonists also stimulated Eomes-dependent CD226 loss that limited the anti-tumor efficacy of this treatment. Thus, CD226 loss restrains CD8+ T cell function and limits the efficacy of cancer immunotherapy.

NK cells with adhesion defects and reduced cytotoxic functions are associated with a poor prognosis in Multiple Myeloma.

The promising results obtained with immunotherapeutic approaches for multiple myeloma (MM) call for a better stratification of patients based on immune components. The most pressing being cytotoxic lymphocytes such as Natural Killer (NK) cells that are mandatory for MM surveillance and therapy. In this study, we performed a single cell RNA sequencing analysis of NK cells from 10 MM patients and 10 age/sex matched healthy donors (HD) that revealed important transcriptomic changes in NK cell landscape affecting both the bone marrow and peripheral blood compartment. The frequency of mature cytotoxic "CD56dim" NK cell subsets was reduced in MM patients at the advantage of late-stage NK cell subsets expressing NFB and IFN-I inflammatory signatures. These NK cell subsets accumulating in MM patients were characterized by a low CD16 and CD226 expression and poor cytotoxic functions. MM CD16/CD226Lo NK cells also had adhesion defects with reduced LFA-1 integrin activation and actin polymerization that may account for their limited effector functions in vitro. Finally, analysis of BM infiltrating NK cells in a retrospective cohort of 177 MM patients from the IFM 2009 trial demonstrated that a high frequency of NK cells and their low CD16 and CD226 expression were associated with a shorter overall survival. Thus, CD16/CD226Lo NK cells with reduced effector functions accumulate along MM development and negatively impact patients' clinical outcome. Given the growing interest in harnessing NK cells to treat myeloma, this improved knowledge around MM-associated NK cell dysfunction will stimulate the development of more efficient immunotherapeutic drugs against MM.

SAR442085, a novel anti-CD38 antibody with enhanced antitumor activity against multiple myeloma.

Anti-CD38 monoclonal antibodies (mAbs) represent a breakthrough in the treatment of multiple myeloma (MM), yet some patients fail to respond or progress quickly with this therapy, highlighting the need for novel approaches. In this study we compared the preclinical efficacy of SAR442085, a next-generation anti-CD38 mAb with enhanced affinity for activating Fcγ receptors (FcγR), with first-generation anti-CD38 mAb daratumumab and isatuximab. In surface plasmon resonance and cellular binding assays, we found that SAR442085 had higher binding affinity than daratumumab and isatuximab for FcγRIIa (CD32a) and FcγRIIIa (CD16a). SAR442085 also exhibited better in vitro antibody-dependent cellular cytotoxicity (ADCC) against a panel of MM cells expressing variable CD38 receptor densities including MM patients' primary plasma cells. The enhanced ADCC of SAR442085 was confirmed using NK-92 cells bearing low and high affinity FcγRIIIa (CD16a)-158F/V variants. Using MM patients' primary bone marrow cells, we confirmed that SAR442085 had an increased ability to engage FcγRIIIa, resulting in higher natural killer (NK) cell activation and degranulation against primary plasma cells than preexisting Fc wild-type anti-CD38 mAbs. Finally, using huFcgR transgenic mice that express human Fcγ receptors under the control of their human regulatory elements, we demonstrated that SAR442085 had higher NK cell-dependent in vivo antitumor efficacy and better survival than daratumumab and isatuximab against EL4 thymoma or VK*MYC myeloma cells overexpressing human CD38. These results highlight the preclinical efficacy of SAR442085 and support the current evaluation of this next-generation anti-CD38 antibody in phase I clinical development in patients with relapsed/refractory MM.

TIGIT immune checkpoint blockade restores CD8+ T-cell immunity against multiple myeloma.

Immune-based therapies hold promise for the treatment of multiple myeloma (MM), but so far, immune checkpoint blockade targeting programmed cell death protein 1 has not proven effective as single agent in this disease. T-cell immunoglobulin and ITIM domains (TIGIT) is another immune checkpoint receptor known to negatively regulate T-cell functions. In this study, we investigated the therapeutic potential of TIGIT blockade to unleash immune responses against MM. We observed that, in both mice and humans, MM progression was associated with high levels of TIGIT expression on CD8+ T cells. TIGIT+ CD8+ T cells from MM patients exhibited a dysfunctional phenotype characterized by decreased proliferation and inability to produce cytokines in response to anti-CD3/CD28/CD2 or myeloma antigen stimulation. Moreover, when challenged with Vk*MYC mouse MM cells, TIGIT-deficient mice showed decreased serum monoclonal immunoglobulin protein levels associated with reduced tumor burden and prolonged survival, indicating that TIGIT limits antimyeloma immune responses. Importantly, blocking TIGIT using monoclonal antibodies increased the effector function of MM patient CD8+ T cells and suppressed MM development. Altogether our data provide evidence for an immune-inhibitory role of TIGIT in MM and support the development of TIGIT-blocking strategies for the treatment of MM patients.

Elucidation of the Na(2/3)FePO4 and Li(2/3)FePO4 intermediate superstructure revealing a pseudouniform ordering in 2D.

Based on TEM, synchrotron X-ray diffraction, DFT calculations, and Mössbauer spectroscopy, a unified understanding of the Na and Li intercalation process in FePO4 is proposed. The key to this lies in solving the highly sought-after intermediate A(2/3)FePO4 (A = Na, Li) superstructures that are characterized by alkali ions as well as Fe(II)/Fe(III) charge orderings in a monoclinic three-fold supercell. Formation energies and electrochemical potential calculations confirm that Na(2/3)FePO4 and Li(2/3)FePO4 are stable and metastable, respectively, and that they yield insertion potentials in fair agreement with experimental values. The 2/3 Na(Li) and 1/3 vacancy sublattice of the intermediate phases forms a dense (101)(Pnma) plane in which the atom/vacancy ordering is very similar to that predicted for the most uniform distribution of 1/3 of vacancies in a 2D square lattice. Structural analysis strongly suggests that the key role of this dense plane is to constrain the intercalation in the diffusion channels to operate by cooperative filling of (bc)(Pnma). From a practical point of view, this generalized mechanism highlights the fact that an interesting strategy for obtaining high-rate FePO4 materials would consist in designing grains with an enhanced (101) surface area, thereby offering potential for substantial improvements with respect to the performance of rechargeable Li and Na batteries.

Interphase evolution at two promising electrode materials for Li-ion batteries: LiFePO4 and LiNi1/2 Mn1/2O2.

The present review reports the characterization and control of interfacial processes occurring on olivine LiFePO(4) and layered LiNi(1/2) Mn(1/2)O(2), standing here as model compounds, during storage and electrochemical cycling. The formation and evolution of the interphase created by decomposition of the electrolyte is investigated by using spectroscopic tools such as magic-angle-spinning nuclear magnetic resonance ((7)Li,(19)F and (31)P) and electron energy loss spectroscopy, in parallel to X-ray photoelectron spectroscopy, to quantitatively describe the interphase and unravel its architecture. The influence of the pristine surface chemistry of the active material is carefully examined. The importance of the chemical history of the surface of the electrode material before any electrochemical cycling and the strong correlation between interface phenomena, the formation/evolution of an interphase, and the electrochemical behavior appear clearly from the use of these combined characterization probes. This approach allows identifying interface aging and failure mechanisms. Different types of surface modifications are then investigated, such as intrinsic modifications upon aging in air or methods based on the use of additives in the electrolyte or carbon coatings on the surface of the active materials. In each case, the species detected on the surface of the materials during storage and cycling are correlated with the electrochemical performance of the modified positive electrodes.

Reaction mechanisms for electrolytic manganese dioxide in rechargeable aqueous zinc-ion batteries.

This study reports the phase transformation behaviour associated with electrolytic manganese dioxide (EMD) utilized as the positive electrode active material for aqueous zinc-ion batteries. Electrochemical techniques, including galvanostatic charge-discharge and rotating ring-disk electrode measurements, and microstructural techniques, using X-ray powder diffraction, scanning electron microscopy, and transmission/scanning transmission electron microscopy, were utilized to characterize the positive electrode at different stages of discharge and charge of zinc-ion cells. The results indicate that, during discharge, a fraction of EMD undergoes a transformation to ZnMn2O4 (spinel-type) and Zn2+ is intercalated into the tunnels of the γ- and ε-MnO2 phases, forming ZnxMnO2 (tunnel-type). When a critical concentration of Mn3+ in the intercalated ZnxMnO2 species is reached, a disproportionation/dissolution reaction is triggered leading to the formation of soluble Mn2+ and hydroxide (OH-) ions; the latter precipitates as zinc hydroxide sulfate (ZHS, Zn4(OH)6(SO4)·5H2O) by combination with the ZnSO4/H2O electrolyte. During charge, Zn2+ is reversibly deintercalated from the intergrown tunneled phases (γ-/ε-ZnxMnO2), Mn2+ is redeposited as layered chalcophanite (ZnMn3O7·3H2O), and ZHS is decomposed by protons (H+) formed during the electrochemical deposition of chalcophanite.

Stepwise surface encoding for high-throughput assembly of nanoclusters.

Self-assembly offers a promising method to organize functional nanoscale objects into two-dimensional (2D) and 3D superstructures for exploiting their collective effects. On the other hand, many unique phenomena emerge after arranging a few nanoscale objects into clusters, the so-called artificial molecules. The strategy of using biomolecular linkers between nanoparticles has proven especially useful for construction of such nanoclusters. However, conventional solution-based reactions typically yield a broad population of multimers or isomers of clusters; furthermore, the efficiency of fabrication is often limited. Here, we describe a novel high-throughput method for designing and fabricating clusters using DNA-encoded nanoparticles assembled on a solid support in a stepwise manner. This method efficiently imparts particles with anisotropy during their assembly and disassembly at a surface, generating remarkably high yields of well-defined dimer clusters and Janus (two-faced) nanoparticles. The method is scalable and modular, assuring large quantities of clusters of designated sizes and compositions.

Rational design of sulphur host materials for Li-S batteries: correlating lithium polysulphide adsorptivity and self-discharge capacity loss.

A versatile, cost-effective electrochemical analysis strategy is described that determines the specific S(n)(2-) adsorptivity of materials, and allows prediction of the long-term performance of sulphur composite electrodes in Li-S cells. Measurement of nine different materials with varying surface area, and hydrophobicity using this protocol determined optimum properties for capacity stabilization.

Surface-enhanced redox chemistry of polysulphides on a metallic and polar host for lithium-sulphur batteries.

The lithium-sulphur battery relies on the reversible conversion between sulphur and Li2S and is highly appealing for energy storage owing to its low cost and high energy density. Porous carbons are typically used as sulfur hosts, but they do not adsorb the hydrophilic polysulphide intermediates or adhere well to Li2S, resulting in pronounced capacity fading. Here we report a different strategy based on an inherently polar, high surface area metallic oxide cathode host and show that it mitigates polysulphide dissolution by forming an excellent interface with Li2S. Complementary physical and electrochemical probes demonstrate strong polysulphide/Li2S binding with this 'sulphiphilic' host and provide experimental evidence for surface-mediated redox chemistry. In a lithium-sulphur cell, Ti4O7/S cathodes provide a discharge capacity of 1,070 mAh g(-1) at intermediate rates and a doubling in capacity retention with respect to a typical conductive carbon electrode, at practical sulphur mass fractions up to 70 wt%. Stable cycling performance is demonstrated at high rates over 500 cycles.

Tailoring porosity in carbon nanospheres for lithium-sulfur battery cathodes.

Porous hollow carbon spheres with different tailored pore structures have been designed as conducting frameworks for lithium-sulfur battery cathode materials that exhibit stable cycling capacity. By deliberately creating shell porosity and utilizing the interior void volume of the carbon spheres, sufficient space for sulfur storage as well as electrolyte pathways is guaranteed. The effect of different approaches to develop shell porosity is examined and compared in this study. The most highly optimized sulfur-porous carbon nanosphere composite, created using pore-formers to tailor shell porosity, exhibits excellent cycling performance and rate capability. Sulfur is primarily confined in 4-5 nm mesopores in the carbon shell and inner lining of the shells, which is beneficial for enhancing charge transfer and accommodating volume expansion of sulfur during redox cycling. Little capacity degradation (∼0.1% /cycle) is observed over 100 cycles for the optimized material.