ABSTRACT
Despite the success of immunotherapy, overcoming immunoresistance in cancer remains challenging. We identified a unique niche of tumor-associated macrophages (TAMs), coexpressing T cell immunoglobulin and mucin domain-containing 3 (TIM3) and V-domain immunoglobulin suppressor of T cell activation (VISTA), that dominated human and mouse tumors resistant to most of the currently used immunotherapies. TIM3+VISTA+ TAMs were sustained by IL-4-enriching tumors with low (neo)antigenic and T cell-depleted features. TIM3+VISTA+ TAMs showed an anti-inflammatory and protumorigenic phenotype coupled with inability to sense type I interferon (IFN). This was established with cancer cells succumbing to immunogenic cell death (ICD). Dying cancer cells not only triggered autocrine type I IFNs but also exposed HMGB1/VISTA that engaged TIM3/VISTA on TAMs to suppress paracrine IFN-responses. Accordingly, TIM3/VISTA blockade synergized with paclitaxel, an ICD-inducing chemotherapy, to repolarize TIM3+VISTA+ TAMs to proinflammatory TAMs that killed cancer cells via tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) signaling. We propose targeting TIM3+VISTA+ TAMs to overcome immunoresistant tumors.
Subject(s)
Hepatitis A Virus Cellular Receptor 2 , Immunotherapy , Tumor-Associated Macrophages , Tumor-Associated Macrophages/metabolism , Tumor-Associated Macrophages/immunology , Tumor-Associated Macrophages/drug effects , Animals , Hepatitis A Virus Cellular Receptor 2/metabolism , Humans , Immunotherapy/methods , Mice , Drug Resistance, Neoplasm , Neoplasms/therapy , Neoplasms/immunology , Neoplasms/drug therapy , Neoplasms/pathology , Cell Line, Tumor , Tumor Microenvironment/immunology , Interferon Type I/metabolism , B7 AntigensABSTRACT
Epstein-Barr Virus (EBV), is a ubiquitous γ-Herpesvirus that infects over 95% of the human population and can establish a life-long infection without causing any clinical symptoms in healthy individuals by residing in memory B-cells. Primary infection occurs in childhood and is mostly asymptomatic, however in some young adults it can result in infectious mononucleosis (IM). In immunocompromised individuals however, EBV infection has been associated with many different malignancies. Since EBV can infect both epithelial and B-cells and very rarely NK cells and T-cells, it is associated with both epithelial cancers like nasopharyngeal carcinoma (NPC) and gastric carcinoma (GC), with lymphomas including Burkitt Lymphoma (BL) or Post-transplant Lymphoproliferative Disorder (PTLD) and rarely with NK/T-cell lymphomas. Currently there are no approved antivirals active in PTLD nor in any other malignancy. Moreover, lytic phase disease almost never requires antiviral treatment. Although many novel therapies against EBV have been described, the management and/or prevention of EBV primary infections or reactivations remains difficult. In this review, we discuss EBV infection, therapies targeting EBV in both lytic and latent state with novel therapeutics developed that show anti-EBV activity as well as EBV-associated malignancies both, epithelial and lymphoproliferative malignancies and emerging therapies targeting the EBV-infected cells.
Subject(s)
Antiviral Agents , Epstein-Barr Virus Infections , Herpesvirus 4, Human , Immunocompromised Host , Humans , Epstein-Barr Virus Infections/immunology , Epstein-Barr Virus Infections/virology , Epstein-Barr Virus Infections/drug therapy , Herpesvirus 4, Human/immunology , Antiviral Agents/therapeutic use , AnimalsABSTRACT
PURPOSE OF REVIEW: Posttransplant lymphoproliferative disorder (PTLD) is a serious complication following transplantation from an allogeneic donor. Epstein-Barr Virus (EBV) is involved in a substantial number of cases. In this review, we aim to summarize recent knowledge on pathogenesis, classification and treatment of EBV + PTLD. RECENT FINDINGS: New insights in the complex oncogenic properties of EBV antigens noncoding Ribonucleic acids (RNAs), especially EBV MicroRNA (miRNAs), have increased our knowledge of the pathogenesis of EBV + PTLD. In addition the potential influence of EBV on the tumor microenvironment is becoming clearer, paving the way for new types of immunotherapy. Currently PTLD is classified according to the World Health Organization classification together with other lymphoproliferative disorders, based on the specific immunosuppression. However, a new framework integrating all types of lymphoproliferative disorders in all different settings of immune deficiency and dysregulation is needed. Although treatment of EBV + and EBV - PTLD was largely similar in the past, EBV-directed therapies are currently increasingly used. SUMMARY: The use of EBV-directed therapies and new agents, based on better understanding of pathogenesis and classification of PTLD, will change the treatment landscape of EBV + PTLD in the next era.
