One of the primary goals in tumor immunotherapy is to reset the immune system from tolerogenic to immunogenic – a process in which invariant natural killer T (iNKT) cells are implicated. iNKT cells ...develop in the thymus and perform immunosurveillance against tumor cells peripherally. When optimally stimulated, iNKT cells differentiate and display more efficient immune functions. Some cells survive and act as effector memory cells. We discuss the putative roles of iNKT cells in antitumor immunity, and posit that it may be possible to develop novel therapeutic strategies to treat cancers using iNKT cells. In particular, we highlight the challenge of uniquely energizing iNKT cell-licensed dendritic cells to serve as effective immunoadjuvants for both arms of the immune system, thus coupling immunological networks.
iNKT cell subsets differentiate in the thymus, and iNKT1 cells can play a role in immune surveillance against cancer.Once optimally activated, iNKT1 cells can exert antitumor effects in peripheral tissues.Following activation, memory iNKT cells can differentiate in peripheral organs.Strategies using iNKT cell-licensed dendritic cells may constitute a promising new tool for immune enhancement in cancer immunotherapies.
CCL5 is a unique chemokine with distinct stage and cell-type specificities for regulating inflammation, but how these specificities are achieved and how CCL5 modulates immune responses is not well ...understood. Here we identify two stage-specific enhancers: the proximal enhancer mediates the constitutive CCL5 expression during the steady state, while the distal enhancer located 1.35 Mb from the promoter induces CCL5 expression in activated cells. Both enhancers are antagonized by RUNX/CBFβ complexes, and SATB1 further mediates the long-distance interaction of the distal enhancer with the promoter. Deletion of the proximal enhancer decreases CCL5 expression and augments the cytotoxic activity of tissue-resident T and NK cells, which coincides with reduced melanoma metastasis in mouse models. By contrast, increased CCL5 expression resulting from RUNX3 mutation is associated with more tumor metastasis in the lung. Collectively, our results suggest that RUNX3-mediated CCL5 repression is critical for modulating anti-tumor immunity.
Abstract
Most tumors employ multiple strategies to attenuate T-cell-mediated immune responses. In particular, immune suppression surrounding the tumor is achieved by interfering with ...antigen-presenting cells and effector T cells. Controlling both the tumor and the tumor microenvironment (TME) is critical for cancer treatment. Checkpoint blockade therapy can overcome tumor-induced immune suppression, but more than half of the patients fail to respond to this treatment; therefore, more effective cancer immunotherapies are needed. Generation of an anti-tumor immune response is a multi-step process of immune activation against the tumor that requires effector T cells to recognize and exert toxic effects against tumor cells, for which two strategies are employed—inhibition of various types of immune suppressor cells, such as myeloid cells and regulatory T cells, and establishment of anti-tumor immune surveillance including, activation of natural killer cells and cytotoxic T cells. It was recently shown that anti-cancer drugs not only directly kill tumor cells, but also influence the immune response to cancer by promoting immunogenic cell death, enhancing antigen presentation or depleting immunosuppressive cells. Herein, we review the mechanisms by which tumors exert immune suppression as well as their regulation. We then discuss how the complex reciprocal interactions between immunosuppressive and immunostimulatory cells influence immune cell dynamics in the TME. Finally, we highlight the new therapies that can reverse immune suppression in the TME and promote anti-tumor immunity.
Suppressive networks of immune cells in anti-tumor responses
The efficacy of current coronavirus disease 2019 (COVID‐19) vaccines has been demonstrated; however, emerging evidence suggests insufficient protection in certain immunocompromised cancer patients. ...We previously developed a cell‐based anti‐cancer vaccine platform involving artificial adjuvant vector cells (aAVCs) capable of inducing a strong adaptive response by enhancing the innate immunity. aAVCs are target antigen‐transfected allogenic cells that simultaneously express the natural killer T‐cell ligand–CD1d complex on their surface. In the present study, we applied this system for targeting the severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) spike protein (CoV‐2‐S) using CoV‐2‐S‐expressing aAVCs (aAVC‐CoV‐2) and evaluated the immune response in a murine model. A single dose of aAVC‐CoV‐2 induced a large amount of CoV‐2‐S‐specific, multifunctional CTLs in addition to CD4+ T‐cell‐dependent anti‐CoV‐2‐S‐specific Abs. CoV‐2‐S‐specific CTLs infiltrated the lung parenchyma and persisted as long‐term memory T cells. Furthermore, we immunized mice with CoV‐2‐S‐ and tumor‐associated antigen (TAA)‐co‐expressing aAVCs (aAVC‐TAA/CoV‐2) and evaluated whether the anti‐SARS‐CoV‐2 and antitumor CTLs were elicited. We found that the aAVC‐TAA/CoV‐2‐S therapy exerted apparent antitumor effects and induced CoV‐2‐S‐specific CTLs. These findings suggest aAVC‐TAA/CoV‐2‐S therapy as a promising vaccine candidate for preventing COVID‐19, as well as enhancing the effectiveness of cancer therapies.
Due to the insufficient efficacy of current COVID‐19 vaccines in cancer patients, such high‐risk groups require more efficient vaccines that induce a strong memory response and provide dual protection against cancer and COVID‐19. We showed that SARS‐CoV‐2 spike protein‐expressing artificial adjuvant vector cells (aAVC‐CoV‐2) elicited the production of robust and long‐lived spike protein‐specific multifunctional cytotoxic T lymphocytes (CTLs) capable of infiltrating the lung parenchyma, thus illustrating the distinct advantage of using aAVC‐CoV‐2 as a second‐line vaccine, especially for individuals who are resistant to the current COVID‐19 vaccines. In addition, aAVCs expressing tumor‐associated antigen (TAA) and spike protein caused a dual induction of TAA‐specific CD8+ T cells and spike protein‐specific CD8+ T cells and provided sufficient protection against tumors, suggesting an effective strategy for treating cancer patients while simultaneously preventing SARS‐CoV‐2 infection.
Neuronal activity induces intracellular Ca2+ increase, which triggers activation of a series of Ca2+‐dependent signaling cascades. Among these, the multifunctional Ca2+/calmodulin‐dependent protein ...kinases (CaMKs, or calmodulin kinases) play key roles in neuronal transmission, synaptic plasticity, circuit development and cognition. The most investigated CaMKs for these roles in neuronal functions are CaMKI, CaMKII, CaMKIV and we will shed light on these neuronal CaMKs’ functions in this review. Catalytically active members of CaMKs currently are CaMKI, CaMKII, CaMKIV and CaMKK. Although they all necessitate the binding of Ca2+ and calmodulin complex (Ca2+/CaM) for releasing autoinhibition, each member of CaMK has distinct activation mechanisms—autophosphorylation mediated autonomy of multimeric CaMKII and CaMKK‐dependent phosphoswitch‐induced activation of CaMKI or CaMKIV. Furthermore, each CaMK shows distinct subcellular localization that underlies specific compartmentalized function in each activated neuron. In this review, we first summarize these molecular characteristics of each CaMK as to regulation and subcellular localization, and then describe each biological function. In the last section, we also focus on the emerging role of CaMKs in pathophysiological conditions by introducing the recent studies, especially focusing on drug addiction and depression, and discuss how dysfunctional CaMKs may contribute to the pathology of the neuropsychological disorders.
This article is part of the mini review series “60th Anniversary of the Japanese Society for Neurochemistry”.
CaMKs are master regulators that orchestrate dynamic activity‐dependent protein phosphorylation events during synaptic plasticity, gene expression, and cytoskeletonal remodeling, and thereby critically control a variety of biological and pathological brain functions. We shed light on the most studied isoforms of CaMK, namely CaMKI, II, and IV in this review.
This article is part of the mini review series “60th Anniversary of the Japanese Society for Neurochemistry”.
NY‐ESO‐1 is a cancer/testis antigen expressed in various cancer types. However, the induction of NY‐ESO‐1‐specific CTLs through vaccines is somewhat difficult. Thus, we developed a new type of ...artificial adjuvant vector cell (aAVC‐NY‐ESO‐1) expressing a CD1d‐NKT cell ligand complex and a tumor‐associated antigen, NY‐ESO‐1. First, we determined the activation of invariant natural killer T (iNKT) and natural killer (NK) cell responses by aAVC‐NY‐ESO‐1. We then showed that the NY‐ESO‐1‐specific CTL response was successfully elicited through aAVC‐NY‐ESO‐1 therapy. After injection of aAVC‐NY‐ESO‐1, we found that dendritic cells (DCs) in situ expressed high levels of costimulatory molecules and produced interleukn‐12 (IL‐12), indicating that DCs undergo maturation in vivo. Furthermore, the NY‐ESO‐1 antigen from aAVC‐NY‐ESO‐1 was delivered to the DCs in vivo, and it was presented on MHC class I molecules. The cross‐presentation of the NY‐ESO‐1 antigen was absent in conventional DC‐deficient mice, suggesting a host DC‐mediated CTL response. Thus, this strategy helps generate sufficient CD8+ NY‐ESO‐1‐specific CTLs along with iNKT and NK cell activation, resulting in a strong antitumor effect. Furthermore, we established a human DC‐transferred NOD/Shi‐scid/IL‐2γcnull immunodeficient mouse model and showed that the NY‐ESO‐1 antigen from aAVC‐NY‐ESO‐1 was cross‐presented to antigen‐specific CTLs through human DCs. Taken together, these data suggest that aAVC‐NY‐ESO‐1 has potential for harnessing innate and adaptive immunity against NY‐ESO‐1‐expressing malignancies.
In this study, we developed a new type of artificial adjuvant vector cell (aAVC‐NY‐ESO‐1) expressing a CD1d‐NKT cell ligand complex and a tumor‐associated antigen, NY‐ESO‐1. Although the induction of CTLs by vaccines for NY‐ESO‐1 is believed to be difficult, we successfully showed the NY‐ESO‐1‐specific CTLs by aAVC‐NY‐ESO‐1 therapy. As a key mechanism, we also determined that the NY‐ESO‐1 antigen from aAVC‐NY‐ESO‐1 was delivered to the DCs in situ.
•Galdieria sulphuraria cells absorbed precious metals from HCl solution.•They selectively recovered Au3+ and Pd2+ from aqua regia-based metal wastewater.•Au3+ and Pd2+ can be eluted from G. ...sulphuraria as soluble complexes.•The selective recovery and elution process can be completed within 1h.
The demand for precious metals has increased in recent years. However, low concentrations of precious metals dissolved in wastewater are yet to be recovered because of high operation costs and technical problems. The unicellular red alga, Galdieria sulphuraria, efficiently absorbs precious metals through biosorption. In this study, over 90% of gold and palladium could be selectively recovered from aqua regia-based metal wastewater by using G. sulphuraria. These metals were eluted from the cells into ammonium solutions containing 0.2M ammonium salts without other contaminating metals. The use of G. sulphuraria is an eco-friendly and cost-effective way of recovering low concentrations of gold and palladium discarded in metal wastewater.
The clinical benefits of immune checkpoint blockage (ICB) therapy have been widely reported. In patients with cancer, researchers have demonstrated the clinical potential of antitumor cytotoxic T ...cells that can be reinvigorated or enhanced by ICB. Compared to self-antigens, neoantigens derived from tumor somatic mutations are believed to be ideal immune targets in tumors. Candidate tumor neoantigens can be identified through immunogenomic or immunopeptidomic approaches. Identification of neoantigens has revealed several points of the clinical relevance. For instance, tumor mutation burden (TMB) may be an indicator of immunotherapy. In various cancers, mutation rates accompanying neoantigen loads may be indicative of immunotherapy. Furthermore, mismatch repair-deficient tumors can be eradicated by T cells in ICB treatment. Hence, immunotherapies using vaccines or adoptive T-cell transfer targeting neoantigens are potential innovative strategies. However, significant efforts are required to identify the optimal epitopes. In this review, we summarize the recent progress in the identification of neoantigens and discussed preclinical and clinical studies based on neoantigens. We also discuss the issues remaining to be addressed before clinical applications of these new therapeutic strategies can be materialized.
To decipher dynamic brain information processing, current genetically encoded calcium indicators (GECIs) are limited in single action potential (AP) detection speed, combinatorial spectral ...compatibility, and two-photon imaging depth. To address this, here, we rationally engineered a next-generation quadricolor GECI suite, XCaMPs. Single AP detection was achieved within 3–10 ms of spike onset, enabling measurements of fast-spike trains in parvalbumin (PV)-positive interneurons in the barrel cortex in vivo and recording three distinct (two inhibitory and one excitatory) ensembles during pre-motion activity in freely moving mice. In vivo paired recording of pre- and postsynaptic firing revealed spatiotemporal constraints of dendritic inhibition in layer 1 in vivo, between axons of somatostatin (SST)-positive interneurons and apical tufts dendrites of excitatory pyramidal neurons. Finally, non-invasive, subcortical imaging using red XCaMP-R uncovered somatosensation-evoked persistent activity in hippocampal CA1 neurons. Thus, the XCaMPs offer a critical enhancement of solution space in studies of complex neuronal circuit dynamics.
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•Developing XCaMPs, a spectrally resolved, quadricolor (BGYR) suite of linear GECIs•Resolving PV interneuron spike trains and non-invasive imaging of hippocampal CA1•Cell-type-specific excitation-inhibition dynamics revealed by 3-color fiber photometry•Local dendritic inhibition identified in vivo via paired axon and dendrite recording
Quadricolor suite of genetically encoded calcium indicators for multiplex recording in the brain.
Antigen-specific T cells represent a potential therapeutic avenue for a variety of conditions, but current approaches for generating such cells for therapeutic purposes are limited. In this study, we ...established iPSCs from mature cytotoxic T cells specific for the melanoma epitope MART-1. When cocultured with OP9/DLL1 cells, these iPSCs efficiently generated TCRβ+CD4+CD8+ double positive (DP) cells expressing a T cell receptor (TCR) specific for the MART-1 epitope. Stimulation of these DP cells with anti-CD3 antibody generated a large number of CD8+ T cells, and more than 90% of the resulting cells were specific for the original MART-1 epitope. Stimulation of the CD8+ T cells with MART-1 antigen-presenting cells led to the secretion of IFNγ, demonstrating their specific reactivity. The present study therefore illustrates an approach for cloning and expanding functional antigen-specific CD8+ T cells that might be applicable in cell-based therapy of cancer.
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► iPSCs generated from T cells specific for the MART-1 melanoma epitope ► Differentiation of iPSCs into T cells with a MART-1 specific T cell receptor ► MART-1-based stimulation of T cells demonstrates retained antigen specificity
T cells specific for a tumor antigen made via iPSCs and reprogramming illustrate a potential future approach to cancer immunotherapy.
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