Frontiers in Immunology

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ISSN / EISSN : 1664-3224 / 1664-3224
Published by: Frontiers Media SA (10.3389)
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, Graham Pawelec, Alan Graham Pockley, Pål Johansen
Published: 15 October 2021
Frontiers in Immunology, Volume 12; https://doi.org/10.3389/fimmu.2021.771319

Abstract:
Editorial on the Research Topic:Cancer Vaccines: Time to Think Differently! Although the advent of checkpoint inhibitors has revolutionised immunotherapy, the surge of optimism has been quickly dampened by the fact that only some cancers and only a proportion of cancer patients truly benefit from these treatments when they are administered as a monotherapy. The era of combined therapy is now upon us and many clinical trials are now combining drugs, vaccines and checkpoint inhibitors with the aim to amplify the ability of the immune system to recognize and eradicate cancer. This Frontiers Research Topic entitled “Cancer vaccines: Time to think differently!” has collated 16 contributions from experts who are exploring a range of novel treatment approaches that are centred on vaccine-based approaches for triggering protective anti-cancer immunity in pre-clinical animal models and patients. In a mouse model of head and neck squamous cell carcinoma, Jin et al. show that combining radiation and cetuximab (an epidermal growth factor receptor inhibitor) increased intra-tumoral infiltration of NK cells and CD8+ T cell and enhanced the expression of PD-L1 (checkpoint pathway ligand) by tumour cells. As a consequence, this heightened the susceptibility of the tumour to PD-L1 antibody treatment and thereby increased durable tumour regression and the survival of mice when all three treatments were combined. However, this is only one example of many new and different strategies that are currently being investigated, as has been highlighted in the review article by Chen et al. Although the current focus is very much on ‘checkpoint blockade’, there is no doubt that future combination strategies are likely to include metabolic and epigenetic therapies to circumvent immune escape mechanisms and block intricate immunosuppressive mechanisms in the tumour microenvironment (TME), as discussed by Chen et al. or the use of in situ ablation, as discussed by van den Bijgaart et al. The successful application of platforms employing mRNA-based cancer vaccine technology to SARS-CoV-2 vaccines and the remarkable success of these mRNA-based formulations against COVID-19 has once again highlighted the potency of this novel approach in cancer. This success has reawakened awareness of the potential potency of earlier approaches to vaccines such as the use of dendritic cells (DCs), as shown by Kumbhari et al. who has used a theoretical approach which applies a mathematical model and simulations to demonstrate how vaccine-induced avidity selection can influence tumour clearance. They showed that treatment with immature DCs has the potential to promote the selective expansion of high-avidity cytotoxic T lymphocytes (CTLs) and lead to tumour regression. “Classical” approaches to the generation of DCs for use in immunotherapy may also still leave room for improvement, as discussed by Calmeiro et al. Alternatively, using delivery systems such as the DNA-based ImmunoBody® which directly targets immature DCs in vivo offers the opportunity to simultaneously trigger immunity to two antigens, HAGE and WT1, as described by Almshayakhchi et al. Although predicted epitopes derived from vaccines can be used to monitor CD8+ T cell responses ex vivo in clinical trial settings as a means to gauge the success of T cell vaccines, Lehmann et al. showed that there was no correlation between the ranking of epitopes on the prediction scale and their actual immune dominance. One would therefore need to screen large vaccine-derived peptide pools to increase the accuracy of the targeted response. Data from murine models presented by Bikorimana et al. demonstrate that thymoproteasome-based proteasomal alterations can trigger potent T cell immunity when used as part of an engineered mesenchymal stromal cell-based vaccine. Although vaccination led to the recruitment of macrophages and DCs, the immunotherapeutic effect was mediated by cross-priming-dependent DCs. It was also noted that an interaction between vaccine and monocytes/macrophages impaired T cell activation, as a consequence of which the depletion of monocytes/macrophages prior to vaccination increased efficacy. In an additional article on the use of DC-based vaccines, Stevens et al. review nearly 20 years of DC-based immunotherapy in lung cancer. They conclude that combining DC-based immunotherapy with other cancer therapies, such as chemotherapy, radiotherapy and/or checkpoint inhibition may potentially improve vaccine efficacy. Clinical studies testing these hypotheses are underway. Alternative new and previously considered cancer vaccine delivery approaches are also being (re)-evaluated and discussed in the field. Oladejo et al. consider Listeria monocytogenes as a vaccine vector. They discuss recent clinical experience with Listeria-based immunotherapies and recent advances in the development of improved Listeria-based vaccine platforms and their utilization. In an elegant approach by Otterhaug et al., a subunit cancer vaccine is combined with a photochemical compound in a so-called photochemical internalisation (PCI). The intradermal administration of the vaccine is followed by its uptake into skin antigen presenting cells (APCs). Subsequent light treatment disrupts vaccine-containing endosomes and triggers the release of antigen to the cytosol for presentation to major histocompatibility (MHC) class I molecules and stimulation of CD8+ T cell responses. This first-in-human phase I study in healthy volunteers assessed safety, tolerability, and immune responses to PCI vaccination in combination with the adjuvant poly-ICLC. Another approach to cancer vaccination is presented by Zhang et al. who describe a personalized vaccination regime that could be applied for both the therapeutic and prophylactic treatment of lung cancer. This is based on the derivation of lung cancer cells from induced pluripotent stem cells (iPSCs), which are modified to...
Khalid W. Kalim, Jun-Qi Yang, Vishnu Modur, Phuong Nguyen, Yuan Li, ,
Published: 15 October 2021
Frontiers in Immunology, Volume 12; https://doi.org/10.3389/fimmu.2021.726393

Abstract:
RhoA of the Rho GTPase family is prenylated at its C-terminus. Prenylation of RhoA has been shown to control T helper 17 (Th17) cell-mediated colitis. By characterizing T cell-specific RhoA conditional knockout mice, we have recently shown that RhoA is required for Th2 and Th17 cell differentiation and Th2/Th17 cell-mediated allergic airway inflammation. It remains unclear whether RhoA plays a cell-intrinsic role in regulatory T (Treg) cells that suppress effector T cells such as Th2/Th17 cells to maintain immune tolerance and to promote tumor immune evasion. Here we have generated Treg cell-specific RhoA-deficient mice. We found that homozygous RhoA deletion in Treg cells led to early, fatal systemic inflammatory disorders. The autoimmune responses came from an increase in activated CD4+ and CD8+ T cells and in effector T cells including Th17, Th1 and Th2 cells. The immune activation was due to impaired Treg cell homeostasis and increased Treg cell plasticity. Interestingly, heterozygous RhoA deletion in Treg cells did not affect Treg cell homeostasis nor cause systemic autoimmunity but induced Treg cell plasticity and an increase in effector T cells. Importantly, heterozygous RhoA deletion significantly inhibited tumor growth, which was associated with tumor-infiltrating Treg cell plasticity and increased tumor-infiltrating effector T cells. Collectively, our findings suggest that graded RhoA expression in Treg cells distinguishes tumor immunity from autoimmunity and that rational targeting of RhoA in Treg cells may trigger anti-tumor T cell immunity without causing autoimmune responses.
Shivanthan Shanthikumar, Sarath C. Ranganathan, Richard Saffery,
Published: 15 October 2021
Frontiers in Immunology, Volume 12; https://doi.org/10.3389/fimmu.2021.733217

Abstract:
The immune landscape of the paediatric respiratory system remains largely uncharacterised and as a result, the mechanisms of globally important childhood respiratory diseases remain poorly understood. In this work, we used high parameter flow cytometry and inflammatory cytokine profiling to map the local [bronchoalveolar lavage (BAL)] and systemic (whole blood) immune response in preschool aged children with cystic fibrosis (CF) and aged-matched healthy controls. We demonstrate that children with CF show pulmonary infiltration of CD66b+ granulocytes and increased levels of MIP-1α, MIG, MCP-1, IL-8, and IL-6 in BAL relative to healthy control children. Proportions of systemic neutrophils positively correlated with age in children with CF, whilst systemic CD4 T cells and B cells were inversely associated with age. Inflammatory cells in the BAL from both CF and healthy children expressed higher levels of activation and migration markers relative to their systemic counterparts. This work highlights the utility of multiplex immune profiling and advanced analytical pipelines to understand mechanisms of lung disease in childhood.
Kaiwen Wang, Jiangfeng Zhao, Wanlong Wu, Wenwen Xu, Shuhui Sun, Zhiwei Chen, Yakai Fu, Li Guo, ,
Published: 15 October 2021
Frontiers in Immunology, Volume 12; https://doi.org/10.3389/fimmu.2021.743704

Abstract:
Objective Anti-melanoma differentiation-associated gene 5 (MDA5) autoantibody is a distinctive serology hallmark of dermatomyositis (DM). As an autoantigen, MDA5 is a cytoplasmic RNA recognition receptor. The aim of this study was to address the question of whether the RNA-containing immune complex (IC) formed by MDA5 and anti-MDA5 could activate type I interferon (IFN) response. Method Patients with anti-MDA5+ DM (n = 217), anti-MDA5− DM (n = 68), anti-synthase syndrome (ASyS, n = 57), systemic lupus erythematosus (SLE, n = 245), rheumatoid arthritis (RA, n = 89), and systemic sclerosis (SSc, n = 30) and healthy donors (HD, n = 94) were enrolled in our studies. Anti-MDA5 antibody was detected by line blotting, enzyme-linked immunosorbent assay (ELISA), immunoprecipitation, and Western blotting. Cytokine profiling was determined by multiplex flow cytometry, and IFN-α was further measured by ELISA. Type I IFN-inducible genes were detected by quantitative PCR (qPCR). RNA–IC binding was analyzed by RNA immunoprecipitation. Plasmacytoid dendritic cells (pDCs) derived from healthy donors were cultivated and stimulated with MDA5 ICs with or without RNase and Toll-like receptor 7 (TLR-7) agonist. The interaction between MDA5 ICs and TLR7 was evaluated by immunoprecipitation and confocal microscopy. Results According to our in-house ELISA, the presence of anti-MDA5 antibody in 76.1% of DM patients, along with 14.3% of SLE patients who had a lower titer yet positive anti-MDA5 antibody, was related to the high level of peripheral IFN-α. ICs formed by MDA5 and anti-MDA5 were potent inducers of IFN-α via TLR-7 in an RNA-dependent manner in vitro. Conclusion Our data provided evidence of the mechanistic relevance between the anti-MDA5 antibody and type I IFN pathway.
, Amanda McCormack, Karthik Suresh, Han Woo, Ningchun Xu, Meghan F. Davis, Emily Brigham, Nadia N. Hansel, Meredith C. McCormack, Franco R. D’Alessio
Published: 15 October 2021
Frontiers in Immunology, Volume 12; https://doi.org/10.3389/fimmu.2021.744782

Abstract:
Introduction There is evidence that obesity, a risk factor for asthma severity and morbidity, has a unique asthma phenotype which is less atopic and less responsive to inhaled corticosteroids (ICS). Peripheral blood mononuclear cells (PBMC) are important to the immunologic pathways of obese asthma and steroid resistance. However, the cellular source associated with steroid resistance has remained elusive. We compared the lymphocyte landscape among obese children with asthma to matched normal weight children with asthma and assessed relationship to asthma control. Methods High-dimensional flow cytometry of PBMC at baseline and after dexamethasone stimulation was performed to characterize lymphocyte subpopulations, T-lymphocyte polarization, proliferation (Ki-67+), and expression of the steroid-responsive protein FK506-binding protein 51 (FKBP51). T-lymphocyte populations were compared between obese and normal-weight participants, and an unbiased, unsupervised clustering analysis was performed. Differentially expressed clusters were compared with asthma control, adjusted for ICS and exhaled nitric oxide. Results In the obese population, there was an increased cluster of CD4+ T-lymphocytes expressing Ki-67 and FKBP51 at baseline and CD4+ T-lymphocytes expressing FKBP51 after dexamethasone stimulation. CD4+ Ki-67 and FKBP51 expression at baseline showed no association with asthma control. Dexamethasone-induced CD4+ FKBP51 expression was associated with worse asthma control in obese participants with asthma. FKBP51 expression in CD8+ T cells and CD19+ B cells did not differ among groups, nor did polarization profiles for Th1, Th2, Th9, or Th17 percentage. Discussion Dexamethasone-induced CD4+ FKBP51 expression is uniquely associated with worse asthma control in obese children with asthma and may underlie the corticosteroid resistance observed in this population.
, Nurul Ainaa Adilah Rus Bakarurraini, Siti Nurmi Nasir
Published: 15 October 2021
Frontiers in Immunology, Volume 12; https://doi.org/10.3389/fimmu.2021.740548

Abstract:
Certain cancer therapy has been shown to induce immunogenic cell death in cancer cells and may promote tumor progression instead. The external stress or stimuli may induce cell death and contribute toward the secretion of pro inflammatory molecules. The release of damage-associated molecular patterns (DAMPs) upon induction of therapy or cell death has been shown to induce an inflammatory response. Nevertheless, the mechanism as to how the DAMPs are released and engage in such activity needs further in-depth investigation. Interestingly, some studies have shown that DAMPs can be released through extracellular vesicles (EVs) and can bind to receptors such as toll-like receptors (TCRs). Ample pre-clinical studies have shown that cancer-derived EVs are able to modulate immune responses within the tumor microenvironment. However, the information on the presence of such DAMPs within EVs is still elusive. Therefore, this mini-review attempts to summarize and appraise studies that have shown the presence of DAMPs within cancer-EVs and how it affects the downstream cellular process.
Abigael Eva Chaouat, Barbara Seliger, ,
Published: 15 October 2021
Frontiers in Immunology, Volume 12; https://doi.org/10.3389/fimmu.2021.714799

Abstract:
The coevolution of the human immune system and herpesviruses led to the emergence and diversification of both cellular danger molecules recognized by immune cells on the one hand and viral countermeasures that prevent the expression of these proteins on infected cells on the other. There are eight ligands for the activating receptor NKG2D in humans – MICA, MICB, ULBP1-6. Several of them are induced and surface-expressed on herpesvirus-infected cells to serve as danger signals to activate the immune system. Therefore, these ligands are frequently targeted for suppression by viral immune evasion mechanisms. Mechanisms to downregulate NKG2D ligands and thereby escape immune recognition have been identified in all other human herpesviruses (HHV), except for HHV-6A. In this study, we identify two HHV-6A encoded immunoevasins, U20 and U21, which suppress the expression of the NKG2D ligands ULBP1 and ULBP3, respectively, during infection. Additionally, MICB is targeted by a so far unexplored viral protein. Due to the diminished NKG2D ligand surface expression on infected cells, recognition of HHV-6A infected cells by innate immune cells is impaired. Importantly, our study indicates that immune escape mechanisms between the related herpesviruses HHV-6A and HHV-6B are evolutionary conserved as the same NKG2D ligands are targeted. Our data contribute an additional piece of evidence for the importance of the NKG2D receptor – NKG2D ligand axis during human herpesvirus infections and sheds light on immune evasion mechanisms of HHV-6A.
An-Liang Guo, Jin-Fang Zhao, Lin Gao, Hui-Huang Huang, Ji-Yuan Zhang, Chao Zhang, Jin-Wen Song, Ruo-Nan Xu, Xing Fan, Ming Shi, et al.
Published: 15 October 2021
Frontiers in Immunology, Volume 12; https://doi.org/10.3389/fimmu.2021.757457

Abstract:
Exhaustion of HIV-1-specific CD8+ T cells prevents optimal control of HIV-1 infection. Identifying unconventional CD8+ T cell subsets to effectively control HIV-1 replication is vital. In this study, the role of CD11c+ CD8+ T cells during HIV-1 infection was evaluated. The frequencies of CD11c+ CD8+ T cells significantly increased and were negatively correlated with viral load in HIV-1-infected treatment-naïve patients. HIV-1-specific cells were enriched more in CD11c+ CD8+ T cells than in CD11c- CD8+ T cells, which could be induced by HIV-1-derived overlapping peptides, marking an HIV-1-specific CD8+ T cell population. This subset expressed higher levels of activating markers (CD38 and HLA-DR), cytotoxic markers (granzyme B, perforin, and CD107a), and cytokines (IL-2 and TNF-α), with lower levels of PD-1 compared to the CD11c- CD8+ T cell subset. In vitro analysis verified that CD11c+ CD8+ T cells displayed a stronger HIV-1-specific killing capacity than the CD11c- counterparts. These findings indicate that CD11c+ CD8+ T cells have potent immunotherapeutic efficacy in controlling HIV-1 infection.
Xin Wang, Hongxuan Fan, Yongle Wang, Xufang Yin, Guangying Liu, Chong Gao, Xiaofeng Li,
Published: 15 October 2021
Frontiers in Immunology, Volume 12; https://doi.org/10.3389/fimmu.2021.744254

Abstract:
Patients with rheumatoid arthritis (RA) have a significantly high risk of atrial fibrillation (AF). This study aimed to compare the absolute and relative changes in peripheral T cells in patients with RA who were also affected with and without AF. To help make an early diagnosis and prevent the initiation and progression of AF, the changes in the lymphocyte subsets were assessed in RA patients with and without AF. A propensity score matching (PSM) system (1:3) was used to perform a matched case-control study with 40 RA-AF cases and 120 RA controls. Changes in the erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), anti-citrullinated peptide antibody (ACPA), and rheumatoid factor (RF) were examined. The percentage and absolute number of T, B, natural killer (NK), T helper (Th)1, Th2, Th17, and T-regulatory (Treg) cells in the peripheral blood of patients with and without RA-AF were determined using flow cytometry. Univariate and multivariate analyses were performed to determine the association between peripheral lymphocytes and RA-AF. Demographic data, ESR, CRP, ACPA, and the percentage, as well as the absolute value of B, NK, Th2, and Treg cells, showed no significant differences between the propensity score-matched groups of RA and RA-AF. Meanwhile, the absolute number and percentage of Th1 cells, the absolute number of Th17 cells, the ratio of Th1/Treg, Th17/Treg, and RF were significantly higher in patients with RA-AF than those in the control groups (P < 0.05). Univariate and multivariate logistic regression analyses also revealed that the percentage of Th1 cells, the absolute number of Th17 cells, and the ratio of Th1/Treg were associated with a significantly higher risk of AF. This PSM study demonstrated that the incidence of AF was higher in RA patients with Th cell immunological derangements.
Shuqin Gu, Zhipeng Liu, Li Lin, Shihong Zhong, Yanchen Ma, Xiaoyi Li, Guofu Ye, Chunhua Wen, , Libo Tang
Published: 15 October 2021
Frontiers in Immunology, Volume 12; https://doi.org/10.3389/fimmu.2021.767000

Abstract:
Identification of immunogenic targets against hepatitis B virus (HBV)-encoded proteins will provide crucial advances in developing potential antibody therapies. In this study, 63 treatment-naïve patients with chronic HBV infection and 46 patients who achieved hepatitis B surface antigen loss (sAg loss) following antiviral treatment were recruited. Moreover, six patients who transitioned from the hepatitis B e antigen-positive chronic infection phase (eAg+CInf) to the hepatitis phase (eAg+CHep) were enrolled from real-life clinical practice. Additionally, telbivudine-treated eAg+CHep patients and relapsers or responders from an off-treatment cohort were longitudinally studied. The frequencies and function of B cells were assessed by flow cytometry. We devised a peptide array composed of 15-mer overlapping peptides of HBV-encoded surface (S), core (C), and polymerase (P) proteins and performed a screening on B-cell linear epitopes with sera. Naïve B cells and plasmablasts were increased, whereas total memory, activated memory (AM), and atypical memory (AtM) B cells were reduced in sAg- patients compared with sAg+ patients. Importantly, longitudinal observations found that AtM B cells were associated with successful treatment withdrawal. Interestingly, we identified six S-specific dominant epitopes (S33, S34, S45, S76, S78, and S89) and one C-specific dominant epitope (C37) that reacted with the majority of sera from sAg- patients. Of note, more B-cell linear epitopes were detected in CHep patients with alanine aminotransferase (ALT) flares than in nonflare CInf patients, and five B-cell linear epitopes (S4, S5, S10, S11, and S68) were overwhelmingly recognized by ALT flare patients. The recognition rates of epitopes on C and P proteins were significantly increased in CHep patients relative to CInf patients. Strikingly, a statistically significant elevation in the number of positive epitopes was observed when ALT nonflare patients shifted into the flare phase. Moreover, S76 identified at baseline was confirmed to be associated with a complete response after 48 weeks of telbivudine therapy. Taken together, we identified several functional cure-related B-cell linear epitopes of chronic HBV infection, and these epitopes may serve as vaccine candidates to elicit neutralizing antibodies to treat HBV infection.
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