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In this Q&A, Cell Press Community Review Scientific Editor Leia Judge talks to Dr. Clint Allen and Dr. Sandro Santagata about their new papers "Phenotypic plasticity and reduced tissue retention of exhausted tumor-infiltrating T cells following neoadjuvant immunotherapy in head and neck cancer" and "Lymphocyte networks are dynamic cellular communities in the immunoregulatory landscape of lung adenocarcinoma" and their experiences with publishing through Cell Press Community Review. [ABSTRACT FROM AUTHOR]

α-Galactosyl ceramide (GalCer) as a glycolipid has been long used as a standard reference for positive control in natural killer T cell studies. The (1,2)-disaccharide analogue of GalCer attracts a special attention in the study of lysosomal glycolipid processing. This paper describes the synthesis and self-assembly behaviors of GalCer 1,2-polysaccharide analogue (PolyGalCer), having considered the 1,2-disaccharide analogue as a structural motif. The synthesis of PolyGalCer is performed via one-pot glycosidation technique of 1,2-linked oligogalactan exploiting chain polymerization of galactose-based cyclic sulfite as a monomer initiated with ceramide-based alcoholic aglycon. Through the concentration dependence of PolyGalCer solutions in water or in MeOH on the turbidity, it is found that PolyGalCer forms associates in both media. From the intersection points, the critical aggregation concentration (CAC) values of PolyGalCer in water and MeOH were estimated. To know the self-assembly and the thermal transition behaviors, we performed dynamic light scattering (DLS) analysis of the associates comprising PolyGalCer in water. The transmission electron microscopy observations of the aqueous sample solution indicate that the solution of PolyGalCer includes large spherical associates. The results clarify that the 1,2-galactan moiety of PolyGalCer skeleton contributes on the kinetic inhibition of large associate formation and the metamorphosis of associates. [Display omitted] [ABSTRACT FROM AUTHOR]

Hepatitis C virus (HCV) can establish infection via two distinct modes: virus-to-cell infection and cell-to-cell transmission. These infections prompt the activation of two types of adaptive immune responses: the cytotoxic T lymphocyte response and the antibody response. In this paper, we study HCV dynamics by developing a multiscale model that incorporates both modes of infection as well as the two types of immune responses. We derive both the basic reproduction number of virus and four immune reproduction numbers for the model. We identify five equilibria, the existence of which depends on the values of basic reproduction number of virus and the immune reproduction numbers. We also establish the global asymptotic stability of the equilibria by employing Lyapunov functions, which further underscores the profound impact of the aforementioned reproduction numbers on the model's overall stability. [ABSTRACT FROM AUTHOR]

Tumor-associated macrophages (TAMs), the main components of infiltrating leukocytes in tumors, often play a key role in promoting cancer development and progression. The tumor-specific microenvironment forces the phenotype of tumor-infiltrating to evolve in a direction favorable to tumor development, that is, the generation of M2-like TAMs. Consequently, the dual intervention of cancer cells and tumor microenvironment has become a research hotspot in the field of tumor immunotherapy. In this contribution, we developed pH-sensitive mesoporous calcium silicate nanocomposites (MCNs) encapsulated with indocyanine green (ICG) to enable the effective combination of photothermal therapy (PTT) and photodynamic therapy (PDT) triggered by the 808 nm near-infrared (NIR) light. The mannose and hyaluronic acid-grafted MCNs specifically targeted TAMs and tumor cells and promoted cell apoptosis both in vitro and in vivo. This paper revealed that irradiation of ICG loaded MCNs with NIR can produce a potent hyperthermia and induce abundant intracellular singlet oxygen generation in the target cells. These results suggest that the novel nanoplatform is believed to facilitate the delivery of chemotherapeutic agents to the tumor microenvironment (TME) to enhance the effects of tumor treatment. [Display omitted] [ABSTRACT FROM AUTHOR]

In an article in this issue of Developmental Cell and in a second paper in Cancer Cell , Mahadevan et al. demonstrate that KrasG12D suppression remodels the immunosuppressive microenvironment of Kras G12D pancreatic cancers, recruits activated CD8+ cytotoxic T cells, and epigenetically upregulates Fas expression in cancer cells, leading to tumor clearance via Fas/FasL-mediated apoptosis. [ABSTRACT FROM AUTHOR]

Discrete tissue niches are emerging as essential prerequisites enabling cell communication and function in both homeostasis and disease. In a recent Cell paper, Di Pilato et al. identify a unique dendritic cell-cytotoxic T cell crosstalk within the perivascular space that facilitates T cell survival and proliferation and drives anti-tumor activity. [ABSTRACT FROM AUTHOR]

[Display omitted] • Baicalein-loaded mPEG-PLGA nanoparticles with a high drug-loading rate and stability were developed, which has high biocompatibility and low toxicity. • Baicalein enables to inhibition of the TGF-β/Smad and TGF-β/MAPK signaling pathways and reduces the activation of cancer associated fibroblasts. • PMs-Ba could remodel the tumor microenvironment by baicalein-loaded mPEG-PLGA, contributing to enhancing the anti-tumor impact of adriamycin-loaded mPEG-PLGA. Cancer-associated fibroblasts constitute a significant component in the tumor microenvironment, playing a pivotal role in tumor proliferation, invasion, migration, and metastasis. Consequently, therapy combining chemotherapeutic agents with tumor microenvironment (TME) modulators appears to be a promising avenue for cancer treatment. In this paper, a tumor microenvironment-based mPEG-PLGA nanoparticle loaded with baicalein (PMs-Ba) was constructed for the purpose of improving the tumor microenvironment in cases of triple-negative breast cancer. The results demonstrate that, on the one hand, PMs-Ba was able to inhibit the transforming growth factor β(TGF-β) signaling pathway to avoid the activation of cancer-associated fibroblasts (CAFs), thereby influencing the interstitial microenvironment of the tumor. On the other hand, the agent led to an increase in the infiltration of cytotoxic T cells, activating the tumor immune microenvironment. Meanwhile, in the murine breast cancer model, an intravenous injection of PMs-Ba combined with doxorubicin nanoparticles (PMs-ADM) significantly improved the antitumor effectiveness. These results suggest that baicalein encapsulated in nanoparticles may be a promising strategy for modulating the TME and for adjuvant chemotherapy, signifying a potential TME-remodeling nanoformulation that could enhance the antitumor efficacy of nanotherapeutics. [ABSTRACT FROM AUTHOR]

• To demonstrate the Galerkin method's validity, via the accuracy of its predictions using DPDE models. • To structure a process for applying the theoretical framework to find theoretical results. • To show the impacts of diffusion and immune response delay on the model, through bifurcation diagrams. • To determine the steady-state solutions, Hopf points, and the stable and unstable zones. • To illustrate comparisons of the DDE and DPDE approaches through a selection of 2-D and 3-D solution maps. This paper studies a diffusive viral infection system with delayed immune response in the one-domain system. A system of DDE equations was explored, both analytically and numerically, using the Galerkin method. A condition that helps to find Hopf bifurcation points is determined. Full maps of the Hopf bifurcation points as well regions of stability are constructed and considered in detail. It is shown that the time delay of cytotoxic T lymphocyte (CTL) response and the diffusion parameter can significantly impact upon the stability regions. Furthermore, the influences of the other free values have been examined for their effects on stability. It is found that, as diffusion increases, the CTL response delay increases, and also as the CTL response delay is increased, the Hopf points for both generation rate and activate rate are decreased, whereas the Hopf points for the infection and death rates increased. Moreover, an increase diffusion results in an increase in the Hopf points for growth rate and activation rate, while the Hopf bifurcations are decreased for the death rate of infected cells. Bifurcation diagrams are plotted to show selected examples of limit cycle behavior (periodic oscillation), and 3-D solutions for the three concentrations in the model have been plotted to corroborate all analytical results from the theoretical section. [ABSTRACT FROM AUTHOR]

Malaria is a life-threatening disease caused by infection with Plasmodium parasites. The goal of developing an effective malaria vaccine is yet to be reached despite decades of massive research efforts. CD4+ helper T cells, CD8+ cytotoxic T cells, and γδ T cells are associated with immune responses to both liver-stage and blood-stage Plasmodium infection. The immune responses of T cell-lineages to Plasmodium infection are associated with both protection and immunopathology. Studies with mouse model of malaria contribute to our understanding of host immune response. In this paper, we focus primarily on mouse malaria model with blood-stage Plasmodium berghei infection and review our knowledge of T cell immune responses against Plasmodium infection. Moreover, we also discuss findings of experimental human studies. Uncovering the precise mechanisms of T cell-mediated immunity to Plasmodium infection can be accomplished through further investigations using mouse models of malaria with rodent Plasmodium parasites. Those findings would be invaluable to advance the efforts for development of an effective malaria vaccine. [ABSTRACT FROM AUTHOR]

Prostate brachytherapy (BT), with either low-dose-rate (LDR) or high-dose-rate (HDR), delivers a highly conformal and heterogeneous dose, allowing for dose escalation beyond external beam radiotherapy (EBRT). Whether this different dose deposition results in opportunistic biological changes that could be harnessed to improve outcomes is not well studied. Given the increasing interest in incorporating immunotherapy into prostate cancer treatment, we sought to investigate the impact of prostate BT on the immune system. A scoping review was performed using PubMed and Scopus for papers published between 2011-2021. Search terms used were "brachytherapy" AND "immune" AND "prostate". A total of 62 records were identified. After review, 6 studies were identified for review that included information an immune assessment on patient samples (tissue and/or blood) after prostate BT. 2 LDR studies (N=68) evaluated changes in the peripheral blood following I-125 BT monotherapy. Both studies demonstrated significant increases in peripheral CD3+ T cells and CD4+ T cells post-BT. However, increased circulating CD8+ T cells were observed in only one study. One study also demonstrated significant increases in Treg subsets up to 150 days post-treatment, which may be compensatory to increased cytotoxic T cell titers. 4 HDR studies (N=37) were identified (HDR fraction sizes 10-15 Gy), and all were done in combination with EBRT. Androgen deprivation therapy was included, for select patients, and one study included nivolumab. Three looked at changes in tissue immune infiltrates seen in post-BT biopsies and 1 looked at changes in both tissue and blood. The largest study (N=24) showed a single 10 Gy fraction of HDR converted 80% of "cold" tumors into an "intermediate" or "hot" state, based on a tumor inflammation signature, when comparing a pre-BT biopsy to a biopsy done prior to HDR fraction 2. In another study (N=6) a significant correlation between increased pathologic response (no tumor in ≥ 4/6 cores) and increased CD4+ and CD8+ T cells in prostate tissue as well as CD4+ T cells in the blood was seen (p values not reported). Tumor infiltrating lymphocyte recruitment may be context dependent given a case report demonstrated decreased T cell infiltration post BT+EBRT. Finally, in a separate study (N=6), peripheral blood analysis demonstrated increased CD8+ T cells with an activated phenotype, decreased CD4+/CD8+ T ratio, decreased CD4+ helper T cells, and increased CD4+PD1+ cells at 3 months post-treatment when compared to baseline levels EBRT. Patients with PSA<0.02 at 3 months were also more likely to have increased CD4+ PD1+ T cells. Both LDR and HDR BT can invoke an immune activating phenotype in prostate cancer; however, changes in immunosuppressive cells are also seen. Additional data is needed to understand how to better promote synergy between these changes and improving clinical outcomes. [ABSTRACT FROM AUTHOR]

• A model for HTLV-I infection that includes uninfected & infected CD4+T cells and HTLV-I-specific CD8+T cells. • To better understand the dynamics of HTLV-I infection, we incorporate a CTL immune response delay. • Applying Lyapunov functional procedures to determine global stability by the reproduction numbers R0 and R1. • The model with delay experiences a destabilization of the infected steady state leading to Hopf bifurcation and periodic solutions. • We estimate the length of delay to preserve the stability of bifurcating limit cycle using Nyquist criteria. This paper deals with a four dimensional mathematical model for Human T-cell leukemia virus type-I (HTLV-I) infection that includes delayed CD8+ cytotoxic T-cells (CTLs) immune response. The proposed system has three biologically feasible steady states, namely disease-free steady state, CTL-inactive steady state and an interior steady state. Our theoretical analysis demonstrates that local and global stability analysis are established by the two critical parameters R 0 and R 1 , basic reproduction numbers due to viral infection and due to CTLs immune response, respectively. The disease-free steady state E 0 is globally stable if R 0 ≤ 1 , and the HTLV-I infections are eliminated. The asymptotic-carrier steady state E 1 is globally stable if R 1 ≤ 1 < R 0 , which indicates HTLV-I infection is chronic without persistence of CTLs immune response. The interior steady state E 2 is globally asymptotic stable if R 1 > 1 , which implies that the HTLV-I infection is choric in persistence of CTLs immune response. Due to immune response delay, our proposed model undergoes a destabilization of the interior steady state leading to Hopf bifurcation and periodic oscillations. We estimate the length of time delay that preserve the stability of period-1 limit cycle. We also derived the direction and stability of Hopf bifurcation around the interior steady state by center manifold theory and normal form method. To determine the robustness of the model, we performed normalized forward sensitivity analysis with reference to R 0 and R 1. Our proposed model undergoes Hopf bifurcation with respect to the production rate of uninfected CD4+T cells h , removal rate of virus-specific CTLs d 4 , spontaneous infected CD4+T cell activation d 2 and transmissibility coefficient β. Implications of our numerical illustrations to the pathogenesis of HTLV-I infection and the development of HTLV-I related HAM/TSP are explored. [ABSTRACT FROM AUTHOR]

SARS-CoV-2 infection intrigued medicine with diverse outcomes ranging from asymptomatic to severe acute respiratory syndrome (SARS) and death. After more than two years of pandemic, reports of reinfection concern researchers and physicists. Here, we will discuss potential mechanisms that can explain reinfections, including the aggravated ones. The major topics of this hypothesis paper are the disbalance between interferon and antibodies responses, HLA heterogeneity among the affected population, and increased proportion of cytotoxic CD4+ T cells polarization in relation to T follicular cells (Tfh) subtypes. These features affect antibody levels and hamper the humoral immunity necessary to prevent or minimize the viral burden in the case of reinfections. [ABSTRACT FROM AUTHOR]

The complex structure of the tumor microenvironment leads to the poor efficacy of tumor immunotherapy. The therapeutic adjuvant designed to enhance the effect of T cells by acting on the costimulatory molecule tumor necrosis factor superfamily member 9 (TNFSF9) has achieved good results. However, because some tumors are characterized by reduced T-cell infiltration, adjuvants acting on T cells alone may have limitations. On the other hand, the blockade of TNFSF9 reverse signalling can have an antitumor effect by reshaping the tumor microenvironment. Therefore, this paper mainly discusses the current status and potential of TNFSF9 bidirectional signalling in antitumor immunotherapy to provide new ideas for tumor immunotherapy. [ABSTRACT FROM AUTHOR]

• Major immune effector cells like CD8+ T lymphocytes and natural killer cells are able to kill or inhibit Hepatocellular carcinoma (HCC) cells and their cytotoxic ability can be enhanced or down-regulated by certain cytokines or drugs. • HCC cells can impair the function of major immune effector cells through a variety of mechanisms. • Organoids or direct contact cell co-culture especially with primary HCC cells and tumor infiltrating lymphocytes provide better understanding of cell–cell interactions between major immune effector cells and HCC cells. • Immunotherapy like checkpoint inhibitors and adoptive cell transfer showed notable effectiveness and safety in preventing HCC recurrence as adjuvant therapy. Hepatocellular carcinoma (HCC) is the most common liver neoplasm with high morbidity and mortality. Tumor immunotherapy might be promising adjuvant therapy for HCC after surgery. To better develop HCC immunotherapy, comprehensive understanding of cell–cell interactions between immune effector cells and HCC cells remains crucial. To review the existing studies to summarize the cell–cell interactions between major immune effector cells and HCC cells providing new data for HCC immunotherapy. A systematic review was conducted by searching PubMed database covering all papers published in recent five years up to January 2020. The guidelines of the preferred reporting items for systematic reviews were firmly followed. There are 9 studies researching the interactions between CD8+ T lymphocytes and HCC cells and 22 studies researching that between natural killer (NK) cells and HCC cells. Among the 9 studies, 6 studies reported that CD8+ T lymphocytes showed cytotoxicity towards HCC cells while 3 studies found CD8+ T lymphocytes were impaired by HCC cells. Among the 22 studies, 20 studies presented that NK cells could inhibit HCC cells. Two studies were found to report NK cell dysfunction in HCC. Based on the systematic analysis, we concluded that CD8+ T lymphocytes and NK cells can inhibit HCC cells. While in turn, HCC cells can also result in the dysfunction of those effector cells through various mechanisms. Organoids and direct contact cell co-culture with primary HCC cells and TILs should be the most innovative way to investigate the interactions and develop novel immunotherapy. [ABSTRACT FROM AUTHOR]

Oral Lichen Planus (OLP) is a chronic inflammatory disorder whose exact etiology remains unknown. Inflammatory mediators, cytotoxic CD8+ T cells and mast cells have been hypothesized to mediate the pathogenesis of OLP. COVID-19 pandemic caused by SARS-CoV-2 is marked by cytokine storms in the affected patients. Altered T-cell responses marked by exhaustion of T-cell count with hyperaggressive remaining T-cells and presence of cross-reactive antibodies render infected humans as fertile grounds for development of multisystem disorders. In addition, Vitamin D deficiency in COVID-19 patients can further modify the T cell mediated immunity. Increased circulating cytokines and hyperactive CD8+ T cells can alter the oral immune barriers rendering them susceptible to oral disorders. Due to the widespread immune dysregulation, it is possible that patients of COVID-19 may develop OLP in the aftermath or during recovery. The paper explores the pathogenic mechanism behind development OLP as post-COVID condition on account of their target receptor, T-cell responses, cytokine profile, mucosal immune barriers and nutrition deficiency. [ABSTRACT FROM AUTHOR]