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Current paradigms of bone marrow failure (BMF) pathophysiology suggest that immune-mediated destruction of hematopoietic stem and progenitor cells (HSPCs) drives acquired aplastic anemia. In contrast, loss of HSPCs due to senescence and/or apoptosis causes BMF in inherited BMF syndromes. In this issue of the JCI, Casado and colleagues challenge this dichotomous conception by demonstrating that NK cell-dependent, immune-mediated hematopoietic suppression and HSPC clearance drive BMF in Fanconi anemia (FA). They show that genotoxic stress upregulates natural killer group 2 member D ligands (NKG2D-L) on FA HSPCs leading to NK cell cytotoxicity through NKG2D receptor activation. Inhibition of NKG2D-NKG2D-L interactions enhanced FA HSPC clonogenic potential and improved cytopenias in vivo. These results provide alternative targets for the development of immunosuppressive therapies to reduce HSPC loss and mitigate the risk of hematologic malignancies in FA., Bone marrow failure in Fanconi anemia Fanconi anemia (FA) is the most common inherited bone marrow failure syndrome (IBMFS). FA is associated with congenital anomalies, predisposition to hematologic and nonhematologic [...]

Fanconi anemia (FA) is the most prevalent inherited bone marrow failure (BMF) syndrome. Nevertheless, the pathophysiological mechanisms of BMF in FA have not been fully elucidated. Since FA cells are defective in DNA repair, we hypothesized that FA hematopoietic stem and progenitor cells (HSPCs) might express DNA damage-associated stress molecules such as natural killer group 2 member D ligands (NKG2D-Ls). These ligands could then interact with the activating NKG2D receptor expressed in cytotoxic NK or [CD8.sup.+] T cells, which may result in progressive HSPC depletion. Our results indeed demonstrated upregulated levels of NKG2D-Ls in cultured FA fibroblasts and T cells, and these levels were further exacerbated by mitomycin C or formaldehyde. Notably, a high proportion of BM [CD34.sup.+] HSPCs from patients with FA also expressed increased levels of NKG2D-Ls, which correlated inversely with the percentage of [CD34.sup.+] cells in BM. Remarkably, the reduced clonogenic potential characteristic of FA HSPCs was improved by blocking NKG2D-NKG2D-L interactions. Moreover, the in vivo blockage of these interactions in a BMF FA mouse model ameliorated the anemia in these animals. Our study demonstrates the involvement of NKG2D-NKG2D-L interactions in FA HSPC functionality, suggesting an unexpected role of the immune system in the progressive BMF that is characteristic of FA., Introduction Fanconi anemia (FA) is a rare inherited disorder mainly characterized by congenital abnormalities, bone marrow failure (BMF), and cancer predisposition (1). Currently, allogeneic transplantation of hematopoietic stem and progenitor [...]

Understanding the tumor immune microenvironment (TIME) promises to be key for optimal cancer therapy, especially in triple-negative breast cancer (TNBC). Integrating spatial resolution of immune cells with laser capture microdissection gene expression profiles, we defined distinct TIME stratification in TNBC, with implications for current therapies including immune checkpoint blockade. TNBCs with an immunoreactive microenvironment exhibited tumoral infiltration of granzyme [B.sup.+][CD8.sup.+] T cells (Gzm[B.sup.+][CD8.sup.+] T cells), a type 1 IFN signature, and elevated expression of multiple immune inhibitory molecules including indoleamine 2,3-dioxygenase (IDO) and programmed cell death ligand 1 (PD-L1), and resulted in good outcomes. An 'immune-cold' microenvironment with an absence of tumoral [CD8.sup.+] T cells was defined by elevated expression of the immunosuppressive marker B7-H4, signatures of fibrotic stroma, and poor outcomes. A distinct poor-outcome immunomodulatory microenvironment, hitherto poorly characterized, exhibited stromal restriction of [CD8.sup.+] T cells, stromal expression of PD-L1, and enrichment for signatures of cholesterol biosynthesis. Metasignatures defining these TIME subtypes allowed us to stratify TNBCs, predict outcomes, and identify potential therapeutic targets for TNBC., Introduction Triple-negative breast cancer (TNBC) lacks targeted therapies, has high rates of distant recurrence, and poor overall survival for patients. Large-scale gene expression and sequencing studies have revealed high heterogeneity [...]

We previously demonstrated that tumor-infiltrating lymphocytes (TIL) in human breast cancer sometimes form organized tertiary lymphoid structures (TLS) characterized by CXCL13-producing T follicular helper (Tfh) cells. The present study found that [CD4.sup.+] Tfh TIL, [CD8.sup.+] TIL, and TIL-B, colocalizing in TLS, all express the CXCL13 receptor CXCR5. An ex vivo functional assay determined that only activated, functional Thl-oriented Tfh TIL ([PD-1.sup.hi][ICOS.sup.int] phenotype) provide help for immunoglobulin and IFN-[gamma] production. A functional Tfh TIL presence signals an active TLS, characterized by humoral (immunoglobulins, [Ki-67.sup.+] TIL-B in active germinal centers) and cytotoxic ([GZMB.sup.+][CD8.sup.+] and [GZMB.sup.+][CD68.sup.+] TIL plus Th1 gene expression) immune responses. Analysis of active versus inactive TLS in untreated patients revealed that the former are associated with positive clinical outcomes. TLS also contain functional T follicular regulatory (Tfr) TIL, which are characterized by a [CD25.sup.+][CXCR5.sup.+][GARP.sup.+][FOXP3.sup.+] phenotype and a demethylated FOXP3 gene. Functional Tfr inhibited functional Tfh activities via a glycoprotein A repetitions predominant (GARP)-associated TGF-[beta]-dependent mechanism. The activity of tumor-associated TLS was dictated by the relative balance between functional Tfh TIL and functional Tfr TIL. These data provide mechanistic insight into TLS processes orchestrated by functional Th1-oriented Tfh TIL, including TIL-B and [CD8.sup.+] TIL activation and immunological memory generation. Tfh TIL, regulated by functional Tfr TIL, are an expected key target of PD-1/PD-L1 blockade., Introduction Adaptive and innate antitumor immune responses and their exploitation in immunotherapy are recognized as key defenses in the fight against cancer. Across a diversity of tumor types, data support [...]

The pathogenesis of idiopathic nephrotic syndrome (INS) is as yet unknown, but several lines of evidence indicate that the immune system may play a crucial pathogenic role in non-genetic INS. The most important of these are, first, the effectiveness of therapy based on immunosuppression and, second, a vast body of data derived both from experimental models and from patient studies that implicate T cells and more recently B cells as major players in INS pathogenesis. However, recent findings also suggest a direct role of podocytes as drivers of the disease process, and the interplay between the glomerulus and the immune system is still being elucidated. In this review we provide an overview of current knowledge on the role of different components of the immune system in determining disease. Advances in our understanding of the pathogenesis of INS may help drive new, more tailored therapeutic approaches., Author(s): Manuela Colucci [sup.1] , Giorgia Corpetti [sup.1] , Francesco Emma [sup.1] , Marina Vivarelli [sup.1] Author Affiliations: (Aff1) 0000 0001 0727 6809, grid.414125.7, Division of Nephrology and Dialysis, Ospedale [...]

The immunoprevention of cancer and cancer recurrence is an important area of concern for the scientific community and society as a whole. Researchers have been working for decades to develop vaccines with the potential to alleviate these health care and economic burdens. So far, vaccines have made more progress in preventing cancer than in eliminating already established cancer. In particular, vaccines targeting oncogenic viruses, such as the human papillomavirus and the hepatitis B virus, are exceptional examples of successful prevention of virus-associated cancers, such as cervical cancer and hepatocellular carcinoma. Cancer-preventive vaccines targeting nonviral antigens, such as tumor-associated antigens and neoantigens, are also being extensively tested. Here, we review the currently approved preventive cancer vaccines; discuss the challenges in this field by covering ongoing preclinical and clinical human trials in various cancers; and address various issues related to maximizing cancer vaccine benefit., Introduction Globally, the number of new cancer cases is expected to reach nearly 22 million per year by 2030; the challenge of managing the escalating associated costs will be worldwide, [...]