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Artificial intelligence (AI) is a general term that refers to the use of a machine to imitate intelligent behavior for performing complex tasks with minimal human intervention, such as machine learning; this technology is revolutionizing and reshaping medicine. AI has considerable potential to perfect health-care systems in areas such as diagnostics, risk analysis, health information administration, lifestyle supervision, and virtual health assistance. In terms of immunotherapy, AI has been applied to the prediction of immunotherapy responses based on immune signatures, medical imaging and histological analysis. These features could also be highly useful in the management of cancer immunotherapy given their ever-increasing performance in improving diagnostic accuracy, optimizing treatment planning, predicting outcomes of care and reducing human resource costs. In this review, we present the details of AI and the current progression and state of the art in employing AI for cancer immunotherapy. Furthermore, we discuss the challenges, opportunities and corresponding strategies in applying the technology for widespread clinical deployment. Finally, we summarize the impact of AI on cancer immunotherapy and provide our perspectives about underlying applications of AI in the future., Graphical abstract With the increasing of clinical data and advanced AI methodologies, AI-based technologies have the potential to increase the functional roles in cancer immunotherapy response.Image 1

The tumor development and metastasis are closely related to the structure and function of the tumor microenvironment (TME). Recently, TME modulation strategies have attracted much attention in cancer immunotherapy. Despite the preliminary success of immunotherapeutic agents, their therapeutic effects have been restricted by the limited retention time of drugs in TME. Compared with traditional delivery systems, nanoparticles with unique physical properties and elaborate design can efficiently penetrate TME and specifically deliver to the major components in TME. In this review, we briefly introduce the substitutes of TME including dendritic cells, macrophages, fibroblasts, tumor vasculature, tumor-draining lymph nodes and hypoxic state, then review various nanoparticles targeting these components and their applications in tumor therapy. In addition, nanoparticles could be combined with other therapies, including chemotherapy, radiotherapy, and photodynamic therapy, however, the nanoplatform delivery system may not be effective in all types of tumors due to the heterogeneity of different tumors and individuals. The changes of TME at various stages during tumor development are required to be further elucidated so that more individualized nanoplatforms could be designed., Graphical abstract Image 1, Highlights • In responsive to the changes in TME, nanoparticles target tumor microenvironment and enhance the therapeutic effect. • Nanoparticles modulate the activation and maturation of DC. • Nanoparticles could reprogram polarization of TAM and relieve hypoxia. • Nanoparticles could transfer the immunosuppressive TME to immunosupportive.

Immune checkpoint inhibitors (ICI) such as anti-programmed cell death protein 1 (PD-1) or anti-programmed death-ligand 1 (PDL-1) antibodies represent a breakthrough in the treatment of advanced neoplasms such as melanoma, lung, or renal cancer. The therapeutic use of these agents is rapidly growing in both active as well as adjuvant settings. Anti-PD-1 agents such as pembrolizumab or nivolumab target PD-1 present on the surface of T cells and other immune cells, enhancing the antitumoral response. Although they offer a better safety profile than anti-CTLA-4 antibodies such as ipilimumab, immune-related adverse events (irAE) still have an important impact on morbidity during treatment. Gastrointestinal and skin irAE are the most frequent adverse events associated with their use and tend to occur early in treatment. Maculopapular rash and lichenoid dermatitis are among the most common skin irAE, affecting approximately 3%-20% of the patients. Most of these reactions are mild and are easily managed with topical corticosteroids, rendering immunotherapy withdrawal unnecessary. Psoriasis might also be exacerbated or present as de novo, both with nivolumab or pembrolizumab, although the exact incidence rate has not been established. This immune-related psoriasis has also been observed during ipilimumab therapy, but its severity has not been defined according to clinical scales such as the psoriasis area severity index (PASI), body surface area (BSA), or physician's global assessment (PGA). Most published series report mild cases with a good outcome after treatment with topical steroids, ultraviolet B phototherapy, or acitretin. Here, we describe 3 patients with moderate to severe psoriasis related to nivolumab treatment, with a favorable response to apremilast and no impairment of antitumoral efficacy.

Background & Aims Intrahepatic cholangiocarcinoma (iCCA) accounts for a fraction of primary liver cancers but has a 5-year survival rate of only 10%. Immune checkpoint inhibitors are effective in treating many solid cancers, but immune checkpoint inhibitor monotherapy has no clear benefit in iCCA. Mitogen-activated kinase (MEK) inhibitors, such as trametinib, have shown promising results in preclinical studies for iCCA by inhibiting cell proliferation and modifying the tumor microenvironment. This study aimed to show the potential benefit of combining trametinib with anti–programmed cell death protein 1 (PD-1) therapy in different iCCA mouse models. Methods Here, we assessed the in vitro cytotoxicity of trametinib in mouse (SB1 and LD-1) and human (EGI-1) cholangiocarcinoma cell lines. We examined the efficacy of single-agent trametinib, anti–PD-1, and a combination of both in subcutaneous, orthotopic, and plasmid-induced iCCA mouse models. Flow cytometry analysis was used to elucidate changes in the tumor immune microenvironment upon treatment. Whole-exome sequencing (WES) was performed on the SB1 tumor cell line to correlate this preclinical model with iCCAs in patients. Results Trametinib reduced tumor cell growth of SB1, LD-1, and EGI-1 tumor cells in vitro. Trametinib treatment led to up-regulation of major histocompatibility complex (MHC-I) and programmed cell death ligand 1 (PD-L-1) (programmed cell death ligand 1) on tumor cells in vitro. The combination of trametinib and anti–PD-1 reduced tumor burden in several iCCA tumor models and improved survival in SB1 tumor-bearing mice compared with either agent alone. Immunoprofiling of tumor-bearing mice showed an increase of hepatic effector memory CD8+ and CD4+ T cells, as well as an increased degranulation of CD8+ T cells, indicating enhanced cytotoxicity. WES and somatic mutational analysis showed no mutations of KRAS, BRAF, and ERK in SB1 tumor cells, and showed a similar genetic signature of SB1 found in a cohort of patients with iCCA. Conclusions Altogether, our study shows that trametinib improves the immunogenicity of tumor cells by up-regulating MHC-I surface expression. The combination with anti–PD-1 results in optimal treatment efficacy for iCCA. WES of SB1 cells suggests that KRAS wild-type iCCAs also respond to this combination therapy., Graphical abstract

Background & Aims The pathogenesis of immune checkpoint inhibitor (ICI)–colitis remains incompletely understood. We sought to identify key cellular drivers of ICI-colitis and their similarities to idiopathic ulcerative colitis, and to determine potential novel therapeutic targets. Methods We used a cross-sectional approach to study patients with ICI-colitis, those receiving ICI without the development of colitis, idiopathic ulcerative colitis, and healthy controls. A subset of patients with ICI-colitis were studied longitudinally. We applied a range of methods, including multiparameter and spectral flow cytometry, spectral immunofluorescence microscopy, targeted gene panels, and bulk and single-cell RNA sequencing. Results We demonstrate CD8+ tissue resident memory T (TRM) cells are the dominant activated T cell subset in ICI-colitis. The pattern of gastrointestinal immunopathology is distinct from ulcerative colitis at both the immune and epithelial-signaling levels. CD8+ TRM cell activation correlates with clinical and endoscopic ICI-colitis severity. Single-cell RNA sequencing analysis confirms activated CD8+ TRM cells express high levels of transcripts for checkpoint inhibitors and interferon-gamma in ICI-colitis. We demonstrate similar findings in both anti–CTLA-4/PD-1 combination therapy and in anti–PD-1 inhibitor-associated colitis. On the basis of our data, we successfully targeted this pathway in a patient with refractory ICI-colitis, using the JAK inhibitor tofacitinib. Conclusions Interferon gamma–producing CD8+ TRM cells are a pathological hallmark of ICI-colitis and a novel target for therapy., Graphical abstract, We present an analysis of the immunopathology in checkpoint-inhibitor colitis, a common adverse effect of cancer immunotherapy. We used our findings to successfully identify a novel therapy for a case of refractory colitis.

As immune checkpoint inhibitor drugs are being used in the treatment of some cancers, unusual adverse events are being reported, labeled as immune-related adverse events. Various endocrinopathies related to immune-related adverse events have been described, among which hypoparathyroidism is exceedingly rare. We report a case of hypoparathyroidism induced by immune checkpoint drugs, highlighting the need for awareness of this emerging complication.

Targeting immune checkpoints such as programmed cell death protein 1 (PD-1) and programmed death ligand-1 (PD-L1) have been approved for treating melanoma, gastric cancer (GC) and bladder cancer with clinical benefit. Nevertheless, many patients failed to respond to anti-PD-1/PD-L1 treatment, so it is necessary to seek an alternative strategy for traditional PD-1/PD-L1 targeting immunotherapy. Here with the data from The Cancer Genome Atlas (TCGA) and our in-house tissue library, PD-L1 expression was found to be positively correlated with the expression of ubiquitin-specific processing protease 7 (USP7) in GC. Furthermore, USP7 directly interacted with PD-L1 in order to stabilize it, while abrogation of USP7 attenuated PD-L1/PD-1 interaction and sensitized cancer cells to T cell killing in vitro and in vivo. Besides, USP7 inhibitor suppressed GC cells proliferation by stabilizing P53 in vitro and in vivo. Collectively, our findings indicate that in addition to inhibiting cancer cells proliferation, USP7 inhibitor can also downregulate PD-L1 expression to enhance anti-tumor immune response simultaneously. Hence, these data posit USP7 inhibitor as an anti-proliferation agent as well as a novel therapeutic agent in PD-L1/PD-1 blockade strategy that can promote the immune response of the tumor., Graphical abstract This study supports that small molecule USP7 inhibitors may be used as novel promoter of the tumor immune response.Image 1

Highlights • Biological process-associated scores generated from mass spectrometry of serum. • Scores demonstrated acceptable levels of reproducibility. • Scores associated with biological processes and clinical outcome in cancer patients. • Possible application to biomarker studies for treatment or monitoring of disease. • Multiple biological processes assessed from 3 µL of serum., Introduction Most diseases involve a complex interplay between multiple biological processes at the cellular, tissue, organ, and systemic levels. Clinical tests and biomarkers based on the measurement of a single or few analytes may not be able to capture the complexity of a patient’s disease. Novel approaches for comprehensively assessing biological processes from easily obtained samples could help in the monitoring, treatment, and understanding of many conditions. Objectives We propose a method of creating scores associated with specific biological processes from mass spectral analysis of serum samples. Methods A score for a process of interest is created by: (i) identifying mass spectral features associated with the process using set enrichment analysis methods, and (ii) combining these features into a score using a principal component analysis-based approach. We investigate the creation of scores using cohorts of patients with non-small cell lung cancer, melanoma, and ovarian cancer. Since the circulating proteome is amenable to the study of immune responses, which play a critical role in cancer development and progression, we focus on functions related to the host response to disease. Results We demonstrate the feasibility of generating scores, their reproducibility, and their associations with clinical outcomes. Once the scores are constructed, only 3 µL of serum is required for the assessment of multiple biological functions from the circulating proteome. Conclusion These mass spectrometry-based scores could be useful for future multivariate biomarker or test development studies for informing treatment, disease monitoring and improving understanding of the roles of various biological functions in multiple disease settings.

Background & aims The pathogenesis of chronic inflammatory bowel diseases (Crohn’s disease [CD] and ulcerative colitis) involves dysregulated TH1 and TH17 cell responses, which can be targeted therapeutically by the monoclonal antibody Ustekinumab directed against the joint p40 subunit of IL-12 and IL-23. These cytokines may also regulate the differentiation of T follicular helper (TFH) cells, which promote B cell function in germinal centers. However, the role of TFH cells in CD pathogenesis and impact of Ustekinumab therapy on TFH cell fate in patients are poorly defined. Methods Lymphocytes were isolated from peripheral blood (n=45) and intestinal biopsies (n=15) of CD patients or healthy controls (n=21) and analyzed by flow cytometry to assess TFH cell phenotypes and functions ex vivo. In addition, TFH cell differentiation was analyzed in the presence of Ustekinumab in vitro. Results TFH cell frequencies in the intestine as well as peripheral blood were associated with endoscopic as well as biochemical evidence of CD activity. CD patients with clinical response to Ustekinumab, but not those with response to anti-TNF antibodies, displayed reduced frequencies of circulating TFH cells in a concentration-dependent manner while the TFH phenotype was not affected by Ustekinumab therapy. In keeping with this notion, TFH cell differentiation was inhibited by Ustekinumab in vitro while TFH cell maintenance was not affected. Moreover, Ustekinumab therapy resulted in reduced germinal center activity in CD patients in vivo. Conclusions These data implicate TFH cells in the pathogenesis of CD and indicate that Ustekinumab therapy affects TFH cell differentiation, which may influence TFH-mediated immune functions in UST-treated CD patients., Graphical abstract

Graphical abstract, The Src-homology 2 domain containing phosphatase 2 (SHP2) plays a critical role in crucial signaling pathways and is involved in oncogenesis and in developmental disorders. Its structure includes two SH2 domains (N-SH2 and C-SH2), and a protein tyrosine phosphatase (PTP) domain. Under basal conditions, SHP2 is auto-inhibited, with the N-SH2 domain blocking the PTP active site. Activation involves a rearrangement of the domains that makes the catalytic site accessible, coupled to the association between the SH2 domains and cognate proteins containing phosphotyrosines. Several aspects of this transition are debated and competing mechanistic models have been proposed. A crystallographic structure of SHP2 in an active state has been reported (PDB code 6crf), but several lines of evidence suggests that it is not fully representative of the conformations populated in solution. To clarify the structural rearrangements involved in SHP2 activation, enhanced sampling simulations of the autoinhibited and active states have been performed, for wild type SHP2 and its pathogenic E76K variant. Our results demonstrate that the crystallographic conformation of the active state is unstable in solution, and multiple interdomain arrangements are populated, thus allowing association to bisphosphorylated sequences. Contrary to a recent proposal, activation is coupled to the conformational changes of the N-SH2 binding site, which is significantly more accessible in the active sate, rather than to the structure of the central β-sheet of the domain. In this coupling, a previously undescribed role for the N-SH2 BG loop emerged.

The mechanistic target of rapamycin (mTOR) pathway integrates metabolic cues into cell fate decisions. A particularly fateful event during the adaptive immune response is the engagement of a T cell receptor by its cognate antigen presented by an antigen-presenting cell (APC). Here, the induction of adequate T cell activation and lineage specification is critical to mount protective immunity; at the same time, inadequate activation, which could lead to autoimmunity, must be avoided. mTOR forms highly conserved protein complexes 1 and 2 that shape lineage specification by integrating signals originating from TCR engagement, co-stimulatory or co-inhibitory receptors and cytokines and availability of nutrients. If one considers autoimmunity as the result of aberrant lineage specification in response to such signals, the importance of this pathway becomes evident; this provides the conceptual basis for mTOR inhibition in the treatment of systemic autoimmunity, such as systemic lupus erythematosus (SLE). Clinical trials in SLE patients have provided preliminary evidence that mTOR blockade by sirolimus (rapamycin) can reverse pro-inflammatory lineage skewing, including the expansion of Th17 and double-negative T cells and plasma cells and the contraction of regulatory T cells. Moreover, sirolimus has shown promising efficacy in the treatment of refractory idiopathic multicentric Castleman disease, newly characterized by systemic autoimmunity due to mTOR overactivation. Alternatively, mTOR blockade enhances responsiveness to vaccination and reduces infections by influenza virus in healthy elderly subjects. Such seemingly contradictory findings highlight the importance to further evaluate the clinical effects of mTOR manipulation, including its potential role in treatment of COVID-19 infection. mTOR blockade may extend healthy lifespan by abrogating inflammation induced by viral infections and autoimmunity. This review provides a mechanistic assessment of mTOR pathway activation in lineage specification within the adaptive and innate immune systems and its role in health and autoimmunity. We then discuss some of the recent experimental and clinical discoveries implicating mTOR in viral pathogensis and aging.

Approximately 4 million cases of nonmelanoma skin cancer affecting 2.5 million individuals were diagnosed in the United States in 2012, with nearly half being cutaneous squamous cell carcinoma (CSCC).1 Risk factors for the development of CSCC include ultraviolet exposure, older age, and immunosuppression.2 There are no standard guidelines to manage advanced or recurrent CSCC. Various systems have been devised to predict which patients are at high risk of recurrence or metastasis, based on clinical or pathologic characteristics, including the American Joint Committee on Cancer and the Brigham and Women's Hospital staging systems. Management of these cases typically requires multidisciplinary care involving Mohs micrographic surgery, surgical oncology, medical oncology, and radiation oncology. The programmed cell death protein 1 (PD-1) receptor, found on the membranes of T cells, binds to the programmed death ligands 1 and 2 (PD-L1 and PD-L2), which are highly expressed in squamous cell cancers.3 The PD-1/PD-L1 interaction results in deactivation of T cells and thereby reduces anticancer immune surveillance. Increased PD-1 and PD-L1 expression levels have been associated with high-risk CSCC, perineural invasion, and organ transplant–associated CSCC compared with noncancerous skin specimens.4 A recent study examining the PD-1 inhibitor cemiplimab in unresectable and metastatic CSCC yielded response rates of 50% and 47%, respectively, with durable responses exceeding 6 months in more than 50% of patients.5 Subsequently, the US Food and Drug Administration approved cemiplimab for the treatment of unresectable and metastatic CSCC. Although PD-1 inhibition is now the standard of care for metastatic CSCC, its use in combination with other treatment modalities in the definitive setting is not yet well described. Here, we present the case of a patient with a diagnosis of locally advanced CSCC who showed complete response to concurrent radiation therapy and PD-1 inhibition.

Highlights • Chemotherapy, radiotherapy and autoimmune disorder can cause thrombocytopenia in cancer patients. • The implications of platelet transfusion on cancer progression; a “vicious circle”. • Mechanisms and signaling pathways of tumor cell-induced platelet activation. • The strategies and windows of opportunities of platelet transfusion in cancer patients., Chemoradiotherapy and autoimmune disorder often lead to secondary thrombocytopenia in cancer patients, and thus, platelet transfusion is needed to stop or prevent bleeding. However, the effect of platelet transfusion remains controversial for the lack of agreement on transfusion strategies. Before being transfused, platelets are stored in blood banks, and their activation is usually stimulated. Increasing evidence shows activated platelets may promote metastasis and the proliferation of cancer cells, while cancer cells also induce platelet activation. Such a vicious cycle of interaction between activated platelets and cancer cells is harmful for the prognosis of cancer patients, which results in an increased tumor recurrence rate and decreased five-year survival rate. Therefore, it is important to explore platelet transfusion strategies, summarize mechanisms of interaction between platelets and tumor cells, and carefully evaluate the pros and cons of platelet transfusion for better treatment and prognosis for patients with cancer with secondary thrombocytopenia., Graphical abstract Activated platelets further promote tumor cell growth and platelet-derived extracellular vesicles promote tumor angiogenesis. Image, graphical abstract

Inflammation is an established driver of severe SARS-CoV-2 infection and a mechanism linked to the increased susceptibility to fatal COVID-19 demonstrated by patients with cancer. As patients with cancer exhibit a higher level of inflammation compared with the general patient population, patients with cancer and COVID-19 may uniquely benefit from strategies targeted at overcoming the unrestrained pro-inflammatory response. Targeted and non-targeted anti-inflammatory therapies may prevent end-organ damage in SARS-CoV-2-infected patients with cancer and decrease mortality. Here, we review the clinical role of selective inhibition of pro-inflammatory interleukins, tyrosine kinase modulation, anti-tumor necrosis factor agents, and other non-targeted approaches including corticosteroids in their roles as disease-modulating agents in patients with COVID-19 and cancer. Investigation of these therapeutics in this highly vulnerable patient group is posited to facilitate the development of tailored therapeutics for this patient population, aiding the transition of systemic inflammation from a prognostic domain to a source of therapeutic targets.

Highlights • B cells regulate atherosclerotic plaque formation through production of antibodies and cytokines, and effects are subset specific (B1 and B2). • Putative human atheroprotective B1 cells function similarly to murine B1 in their spontaneous IgM antibody production. However, marker strategies in identifying human and murine B1 are different. • IgM antibody to oxidation specific epitopes produced by B1 cells associate with human coronary artery disease. • Neoantigen immunization may be a promising strategy for atherosclerosis vaccine development, but further study to determine relevant antigens still need to be done. • B-cell–targeted therapies, used in treating autoimmune diseases as well as lymphoid cancers, might have potential applications in treating cardiovascular diseases. Short- and long-term cardiovascular effects of these agents need to be assessed., Central Illustration, Summary Because atherosclerotic cardiovascular disease is a leading cause of death worldwide, understanding inflammatory processes underpinning its pathology is critical. B cells have been implicated as a key immune cell type in regulating atherosclerosis. B-cell effects, mediated by antibodies and cytokines, are subset specific. In this review, we focus on elaborating mechanisms underlying subtype-specific roles of B cells in atherosclerosis and discuss available human data implicating B cells in atherosclerosis. We further discuss potential B cell–linked therapeutic approaches, including immunization and B cell–targeted biologics. Given recent evidence strongly supporting a role for B cells in human atherosclerosis and the expansion of immunomodulatory agents that affect B-cell biology in clinical use and clinical trials for other disorders, it is important that the cardiovascular field be cognizant of potential beneficial or untoward effects of modulating B-cell activity on atherosclerosis.

In the Checkmate-025 trial, nivolumab treatment prolonged overall survival among patients with previously treated advanced renal cell carcinoma (RCC) compared with treatment with everolimus. Although effective, nivolumab is associated with immune-related adverse events (irAEs). However, the occurrence of hematological irAEs is rare. Some studies have reported on nivolumab-induced thrombocytopenia. Nivolumab associated thrombocytopenia in almost all patients improved with administration of various drugs. However, there have been only a few cases that have reported death owing to cancer aggravation. In this paper, we have described a case of nivolumab-induced thrombocytopenia after third-line treatment for metastatic RCC.

Highlights •] Tumor-derived exosomes play an eye-catching role in immune escape of tumor cells. •] Exosomes play key role in intercellular communication of tumor progression through their cargo and membrane surface protein. •] Tumor-derived exosomes affect PD-L1 expression in the tumor microenvironment, and tumor cells derived exosomes expressing PD-L1. •] Tumor cells derived exosomal PD-L1 inhabit T cells activation in tumor microenvironment. •] Tumor-derived exosomal PD-L1 are regulated by INF-γ and metastasized by draining lymph nodes., Exosomes are bioactive lipid bilayer vesicles released by most cells to mediate intercellular signal communication. Tumor cells release exosomes transmitting signals cell-to-cell and between cells and organs, which will promote tumor angiogenesis, regulate tumor stromal response, immune response, and enhance tumor cells resistance, while exosomes-derived from immune cells in tumor microenvironment play a key role in inhibiting tumor growth and killing tumor cells. Programmed cell death protein 1 (PD-1) combined with Programmed cell death protein ligand 1(PD-L1) can inhibit the activation of T cells, for tumor cells achieve immune escape by overexpressing PD-L1 and binding PD-1 on T cells. The use of anti-PD-1 / PD-L1 antibodies prevents their binding to a certain extent and partially restores T cell's activity. This article mainly discusses the role of exosomal PD-L1 in tumor progression and therapeutic efficacy after application of clinical antibodies, as well as the relation between different reactivity and immunity set points in cancer patients of different races, with different types and at different stages. Besides, we propose that exosomal PD-L1 may become targets for anti-PD-1 / PD-L1 antibody therapy, biomarkers for liquid biopsy, and drug carriers., Graphical abstract In the presented review article, the authors provide an insightful overview of i) exosomal PD-L1 derived from tumor cells and cells within the tumor microenvironment, ii) the role of exosomal PD-L1 in creating a tumor microenvironment of immune suppression and iii) it's clinical relevance as a possible biomarker in PD-1/PD-L1 checkpoint inhibitor cancer immunotherapy. Authors provide very compelling mechanistic evidence, including the work from Poggio et al., regarding plasma membrane origin of exosomal PD-L1, and the role of IFNγ in PD-L1 induction on exosomes. In addition, in tumor immunotherapy, tumor-derived exosome PD-L1 can be used as a new target and a new biomarker for fluid biopsy to evaluate the applicability.Image, graphical abstract

Highlights • IL-6 class switching provides regulation over pro- and anti-inflammatory responses. • Unregulated IL-6 trans-signaling promotes uncontrolled pro-inflammatory responses. • ADAM-17 regulates class switching between IL-6 trans- and classical-signaling. • Selective ADAM-17 blocking restricts overexpression of pro-inflammatory cytokines. • ADAM-17 may be an antiviral drug target to reduce immunopathology disease severity., Disease fatality associated with Ebola, SARS-CoV and dengue infections in humans is attributed to a cytokine storm that is triggered by excessive pro-inflammatory responses. Interleukin (IL)-6 acts as a mediator between pro- and anti-inflammatory reactivity by initiating trans- and classical-signaling, respectively. Hence, IL-6 is assumed to provide a target for a broad range of antiviral agents. Available immunosuppressive antivirals are directed to control an often exaggerated pro-inflammatory response that gives rise to complex clinical conditions such as lymphocytopenia. It is known that IL-6, via its soluble receptor (sIL-6R), initiates a pro-inflammatory response while an anti-inflammatory response is triggered by the membrane-bound IL-6 receptor (IL-6R). Future antivirals should thus aim to target the mechanism that regulates switching between IL-6 trans- and classical-signaling. In this review, we propose that the tumour necrosis factor-α converting enzyme ADAM-17 could be the master molecule involved in regulating IL-6 class switching and through this in controlling pro- and anti-inflammatory responses to viral antigenic stimuli. Therefore, ADAM-17 should be considered as a potential target molecule for novel antiviral drug discovery that would regulate host reactivity to infection and thereby limit or prevent fatal outcomes.

Summary HDV is a small, defective RNA virus that requires the HBsAg of HBV for its assembly, release, and transmission. Chronic HBV/HDV infection often has a severe clinical outcome and is difficult to treat. The important role of a robust virus-specific T cell response for natural viral control has been established for many other chronic viral infections, but the exact role of the T cell response in the control and progression of chronic HDV infection is far less clear. Several recent studies have characterised HDV-specific CD4+ and CD8+ T cell responses on a peptide level. This review comprehensively summarises all HDV-specific T cell epitopes described to date and describes our current knowledge of the role of T cells in HDV infection. While we now have better tools to study the adaptive anti-HDV-specific T cell response, further efforts are needed to define the HLA restriction of additional HDV-specific T cell epitopes, establish additional HDV-specific MHC tetramers, understand the degree of cross HDV genotype reactivity of individual epitopes and understand the correlation of the HBV- and HDV-specific T cell response, as well as the breadth and specificity of the intrahepatic HDV-specific T cell response.

Graphical abstract, The incidence of the novel coronavirus disease (COVID-19) outbreak caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has brought daunting complications for people as well as physicians around the world. An ever-increasing number of studies investigating the characteristics of the disease, day by day, is shedding light on a new feature of the virus with the hope that eventually these efforts lead to the proper treatment. SARS-CoV-2 activates antiviral immune responses, but in addition may overproduce pro-inflammatory cytokines, causing uncontrolled inflammatory responses in patients with severe COVID-19. This condition may lead to lymphopenia and lymphocyte dysfunction, which in turn, predispose patients to further infections, septic shock, and severe multiple organ dysfunction. Therefore, accurate knowledge in this issue is important to guide clinical management of the disease and the development of new therapeutic strategies in patients with COVID-19. In this review, we provide a piece of valuable information about the alteration of each subtype of lymphocytes and important prognostic factors associated with these cells. Moreover, through discussing the lymphopenia pathophysiology and debating some of the most recent lymphocyte- or lymphopenia-related treatment strategies in COVID-19 patients, we tried to brightening the foreseeable future for COVID-19 patients, especially those with severe disease.

The lungs are directly connected to the external environment, which makes them more vulnerable to infection and injury. They are protected by the respiratory epithelium and immune cells to maintain a dynamic balance. Both innate and adaptive immune cells are involved in the pathogenesis of lung diseases. Mucosal-associated invariant T (MAIT) cells are a subset of unconventional T cells, which have attracted increasing attention in recent years. Although MAIT cells account for a small part of the total immune cells in the lungs, evidence suggests that these cells are activated by T cell receptors and/or cytokine receptors and mediate immune response. They play an important role in immunosurveillance and immunity against microbial infection, and recent studies have shown that subsets of MAIT cells play a role in promoting pulmonary inflammation. Emerging data indicate that MAIT cells are involved in the immune response against SARS-CoV-2 and possible immunopathogenesis in COVID-19. Here, we introduce MAIT cell biology to clarify their role in the immune response. Then we review MAIT cells in human and murine lung diseases, including asthma, chronic obstructive pulmonary disease, pneumonia, pulmonary tuberculosis and lung cancer, and discuss their possible protective and pathological effects. MAIT cells represent an attractive marker and potential therapeutic target for disease progression, thus providing new strategies for the treatment of lung diseases.

Nivolumab is a fully human IgG4 anti–programmed cell death protein 1 (PD-1) receptor antibody that is approved by the US Food and Drug Administration for the treatment of metastatic melanoma, refractory non–small cell lung cancer, angiogenesis inhibitor–resistant renal cell carcinoma, and stem cell transplant–resistant classical Hodgkin lymphoma. The blockade of the PD-1 and programmed cell death ligand 1 pathway, as well as other immune checkpoint receptors, functions to inhibit a negative regulator of T-cell activation, thereby activating T cells and promoting antitumor activity.1 Along with pembrolizumab, another PD-1 receptor inhibitor, these agents are promising in the treatment of many different cancer entities but have been associated with a wide array of cutaneous adverse effects. We report an unusual case of a lichenoid drug eruption, with a distinct inverse distribution in the groin area secondary to nivolumab.

Immune checkpoint inhibitors are a new class of cancer therapeutics that promote antitumor immune responses. Currently US Food and Drug Administration–approved agents target the coregulatory molecules programmed cell death protein 1 (PD-1) and cytotoxic T-lymphocyte–associated protein 4 (CTLA-4) and show significant activity in multiple cancer types. These medications can induce a variety of cutaneous eruptions, the full spectrum of which is not yet completely characterized. Here, we report a case of bullous pemphigoid (BP), which began shortly after initiating treatment with the PD-1 inhibitor nivolumab.

Background X-linked lymphoproliferative disease 1 arises from mutations in the SH2D1A gene encoding SLAM-associated protein (SAP), an adaptor protein expressed in T, natural killer (NK), and NKT cells. Defects lead to abnormalities of T-cell and NK cell cytotoxicity and T cell–dependent humoral function. Clinical manifestations include hemophagocytic lymphohistiocytosis, lymphoma, and dysgammaglobulinemia. Curative treatment is limited to hematopoietic stem cell transplantation, with outcomes reliant on a good donor match. Objectives Because most symptoms arise from defective T-cell function, we investigated whether transfer of SAP gene–corrected T cells could reconstitute known effector cell defects. Methods CD3+ lymphocytes from Sap-deficient mice were transduced with a gammaretroviral vector encoding human SAP cDNA before transfer into sublethally irradiated Sap-deficient recipients. After immunization with the T-dependent antigen 4-hydroxy-3-nitrophenylacetly chicken gammaglobulin (NP-CGG), recovery of humoral function was evaluated through germinal center formation and antigen-specific responses. To efficiently transduce CD3+ cells from patients, we generated an equivalent lentiviral SAP vector. Functional recovery was demonstrated by using in vitro cytotoxicity and T follicular helper cell function assays alongside tumor clearance in an in vivo lymphoblastoid cell line lymphoma xenograft model. Results In Sap-deficient mice 20% to 40% engraftment of gene-modified T cells led to significant recovery of germinal center formation and NP-specific antibody responses. Gene-corrected T cells from patients demonstrated improved cytotoxicity and T follicular helper cell function in vitro. Adoptive transfer of gene-corrected cytotoxic T lymphocytes from patients reduced tumor burden to a level comparable with that seen in healthy donor cytotoxic T lymphocytes in an in vivo lymphoma model. Conclusions These data demonstrate that autologous T-cell gene therapy corrects SAP-dependent defects and might offer an alternative therapeutic option for patients with X-linked lymphoproliferative disease 1.