CD39 is expressed by a wide range of cutaneous T-cell lymphomas.

CD39, an ectoenzyme in the immunosuppressive CD39/CD73/adenosine pathway, known to promote solid tumour outgrowth and spreading, was investigated in both skin and blood compartments of cutaneous T cell lymphomas. CD39 was overexpressed by peripheral blood T-cells in Sezary syndrome and mycosis fungoides, and in skin-infiltrating lymphocytes of Sezary syndrome, mycosis fungoides, subcutaneous panniculitis-like T-cell lymphoma and primary cutaneous CD30-positive lymphoproliferation. Our study emphasizes the interest in using CD39/CD73/adenosine pathway blocking agents for cutaneous T cell lymphomas treatment.

IFNα induces CCR5 in CD4+ T cells of HIV patients causing pathogenic elevation.

BACKGROUND: Among people living with HIV, elite controllers (ECs) maintain an undetectable viral load, even without receiving anti-HIV therapy. In non-EC patients, this therapy leads to marked improvement, including in immune parameters, but unlike ECs, non-EC patients still require ongoing treatment and experience co-morbidities. In-depth, comprehensive immune analyses comparing EC and treated non-EC patients may reveal subtle, consistent differences. This comparison could clarify whether elevated circulating interferon-alpha (IFNα) promotes widespread immune cell alterations and persists post-therapy, furthering understanding of why non-EC patients continue to need treatment. METHODS: Levels of IFNα in HIV-infected EC and treated non-EC patients were compared, along with blood immune cell subset distribution and phenotype, and functional capacities in some cases. In addition, we assessed mechanisms potentially associated with IFNα overload. RESULTS: Treatment of non-EC patients results in restoration of IFNα control, followed by marked improvement in distribution numbers, phenotypic profiles of blood immune cells, and functional capacity. These changes still do not lead to EC status, however, and IFNα can induce these changes in normal immune cell counterparts in vitro. Hypothesizing that persistent alterations could arise from inalterable effects of IFNα at infection onset, we verified an IFNα-related mechanism. The protein induces the HIV coreceptor CCR5, boosting HIV infection and reducing the effects of anti-HIV therapies. EC patients may avoid elevated IFNα following on infection with a lower inoculum of HIV or because of some unidentified genetic factor. CONCLUSIONS: Early control of IFNα is essential for better prognosis of HIV-infected patients.

The treatment for HIV, known as antiretroviral therapy (ART), does not cure HIV but enables individuals to live longer, healthier lives. In this study, we compared immune responses between elite controllers (ECs), who control their HIV infection without any treatment, and ART-treated and untreated patients. We demonstrate that IFNα, a small protein crucial in controlling immune system, is excessively produced at the onset of HIV infection and at levels that persist, resulting in poor HIV control without therapy. We show a mechanism for lack of control of HIV by IFNα. While inhibiting HIV, IFNα also simultaneously increases the HIV co-receptor, CCR5, thereby facilitating virus entry into the target cell. This is avoided by ECs which we hypothesize is associated with a lower infectious inoculum of HIV.

Early elevated IFNα is a key mediator of HIV pathogenesis.

BACKGROUND: A complete understanding of the different steps of HIV replication and an effective drug combination have led to modern antiretroviral regimens that block HIV replication for decades, but these therapies are not curative and must be taken for life. "Elite controllers" (ECs) is a term for the 0.5% of HIV-infected persons requiring no antiretroviral therapy, whose status may point the way toward a functional HIV cure. Defining the mechanisms of this control may be key to understanding how to replicate this functional cure in others. METHODS: In ECs and untreated non-EC patients, we compared IFNα serum concentration, distribution of immune cell subsets, and frequency of cell markers associated with immune dysfunction. We also investigated the effect of an elevated dose of IFNα on distinct subsets within dendritic cells, natural killer cells, and CD4+ and CD8 + T cells. RESULTS: Serum IFNα was undetectable in ECs, but all immune cell subsets from untreated non-EC patients were structurally and functionally impaired. We also show that the altered phenotype and function of these cell subsets in non-EC patients can be recapitulated when cells are stimulated in vitro with high-dose IFNα. CONCLUSIONS: Elevated IFNα is a key mediator of HIV pathogenesis.

Currently, HIV infection is not curable, but infected individuals can manage their condition by taking daily doses of antiretroviral therapy. Some individuals, known as elite controllers (ECs), control their infection without antiretroviral treatment, and studying how their immune system responds to HIV exposure could lead to a potential cure for others. Here, we compare immune cell responses between ECs and untreated non-ECs. We find that IFNα, a small protein with an important role in controlling white blood cell activity, is produced in excess in immune cells from non-ECs compared with ECs during early infection. This insight provides an important clue for the future development of a targeted cure for HIV.

Identification of CD160-TM as a tumor target on triple negative breast cancers: possible therapeutic applications.

BACKGROUND: Despite major therapeutic advances, triple-negative breast cancer (TNBC) still presents a worth prognosis than hormone receptors-positive breast cancers. One major issue relies in the molecular and mutational heterogeneity of TNBC subtypes that is reinforced by the absence of reliable tumor-antigen that could serve as a specific target to further promote efficient tumor cell recognition and depletion. CD160 is a receptor mainly expressed by NK lymphocytes and presenting two isoforms, namely the GPI-anchored form (CD160-GPI) and the transmembrane isoform (CD160-TM). While CD160-GPI is constitutively expressed on resting cells and involved in the generation of NK cells' cytotoxic activity, CD160-TM is neo-synthesized upon activation and promotes the amplification of NK cells' killing ability. METHODS: CD160 expression was assessed by immunohistochemistry (IHC) and flow cytometry on TNBC patient biopsies or cell lines, respectively. Antibody (Ab)-mediated tumor depletion was tested in vitro by performing antibody-dependent cell cytotoxicity (ADCC) and phagocytosis (ADCP) assays, and in vivo on a TNBC mouse model. RESULTS: Preliminary data obtained by IHC on TNBC patients' tumor biopsies revealed an unconventional expression of CD160 by TNBC tumor cells. By using a specific but conformation-dependent anti-CD160-TM Ab, we established that CD160-TM, but not CD160-GPI, was expressed by TNBC tumor cells. A conformation-independent anti-CD160-TM mAb (22B12; muIgG2a isotype) was generated and selected according to pre-defined specificity and functional criterions. In vitro functional assays demonstrated that ADCC and ADCP could be induced in the presence of 22B12, resulting in TNBC cell line apoptosis. The ability of 22B12 to exert an in vivo anti-tumor activity was also demonstrated on a TNBC murine model. CONCLUSIONS: Our data identify CD160-TM as a tumor marker for TNBC and provide a rational for the use of anti-CD160-TM antibodies as therapeutic tools in this tumor context.

The HLA-B*57:01 allele corresponds to a very large MHC haploblock likely explaining its massive effect for HIV-1 elite control.

Introduction: We have reanalyzed the genomic data of the International Collaboration for the Genomics of HIV (ICGH), centering on HIV-1 Elite Controllers. Methods: We performed a genome-wide Association Study comparing 543 HIV Elite Controllers with 3,272 uninfected controls of European descent. Using the latest database for imputation, we analyzed 35,552 Single Nucleotide Polymorphisms (SNPs) within the Major Histocompatibility Complex (MHC) region. Results: Our analysis identified 2,626 SNPs significantly associated (p<5. 10-8) with elite control of HIV-1 infection, including well-established MHC signals such as the rs2395029-G allele which tags HLA-B*57:01. A thorough investigation of SNPs in linkage disequilibrium with rs2395029 revealed an extensive haploblock spanning 1.9 megabases in the MHC region tagging HLA-B*57:01, comprising 379 SNP alleles impacting 72 genes. This haploblock contains damaging variations in proteins like NOTCH4 and DXO and is also associated with a strong differential pattern of expression of multiple MHC genes such as HLA-B, MICB, and ZBTB12. The study was expanded to include two cohorts of seropositive African-American individuals, where a haploblock tagging the HLA-B*57:03 allele was similarly associated with control of viral load. The mRNA expression profile of this haploblock in African Americans closely mirrored that in the European cohort. Discussion: These findings suggest that additional molecular mechanisms beyond the conventional antigen-presenting role of class I HLA molecules may contribute to the observed influence of HLA-B*57:01/B*57:03 alleles on HIV-1 elite control. Overall, this study has uncovered a large haploblock associated with HLA-B*57 alleles, providing novel insights into their massive effect on HIV-1 elite control.

Fc receptors act as innate immune receptors during infection?

Innate immunity constitutes the first nonspecific immunological line of defense against infection. In this response, a variety of mechanisms are activated: the complement system, phagocytosis, and the inflammatory response. Then, adaptive immunity is activated. Major opsonization mediators during infections are immunoglobulins (Igs), the function of which is mediated through Fc receptors (FcRs). However, in addition to their role in adaptive immunity, FcRs have been shown to play a role in innate immunity by interacting directly with bacteria in the absence of their natural ligands (Igs). Additionally, it has been hypothesized that during the early phase of bacterial infection, FcRs play a protective role via innate immune functions mediated through direct recognition of bacteria, and as the infection progresses to later phases, FcRs exhibit their established function as receptors in adaptive immunity. This review provides detailed insight into the potential role of FcRs as innate immune mediators of the host defense against bacterial infection independent of opsonins.

IFNα induces CCR5 in CD4+ T-cells, causing its anti- HIV inefficiency and its subsequent pathogenic elevation, partially controlled by anti-HIV therapy.

Like EC, we find that ART-treated patients control serum IFNα concentration and show few immune cell alterations enabling a healthy but fragile medical status. However, treatment interruption leads to elevated IFNα reflecting virus production indicating that like EC, ART does not achieve a virological cure. The immune system becomes overwhelmed by multiple immune cell abnormalities as found in untreated patients. These are chiefly mediated by elevated IFNα inducing signaling checkpoints abnormalities, including PD1, in cytotoxic immune cells. Importantly, during acute infection, elevated IFNα correlated with HIV load and we found that IFNα enhances CCR5, the HIV coreceptor in CD4+ T-cells, impairing its anti-viral response and accounting for the pathogenic vicious cycle: HIV → IFNα ↗ → infected CD4+ T-cells ↗ →HIV ↗. This study opens immunotherapeutic perspectives showing the need to control IFNα in order to convert ART patients into EC.

Early Elevated IFNα Identified as the Key Mediator of HIV Pathogenesis and its low level a Hallmark of Elite Controllers.

Advances in HIV therapy came from understanding its replication. Further progress toward "functional cure" -no therapy needed as found in Elite Controllers (EC)- may come from insights in pathogenesis and avoidance by EC. Here we show that all immune cells from HIV-infected persons are impaired in non-EC, but not in EC. Since HIV infects few cell types, these results suggest an additional mediator of pathogenesis. We identify that mediator as elevated pathogenic IFNα, controlled by EC likely by their preserved potent NK-cells and later by other killer cells. Since the earliest days of infection predict outcome genetic or chance events must be key to EC, and since we found no unique immune parameter at the onset, we suggest a chance infection with a lower HIV inoculum. These results offer an additional approach toward functional cure: a judicious targeting of IFNα for all non-EC patients.

Modulation of NK cell activation by exogenous calcium from alginate dressings in vitro.

Natural Killer (NK) cells participate in the defense against infection by killing pathogens and infected cells and secreting immuno-modulatory cytokines. Defects in NK cell activity have been reported in obese, diabetic, and elderly patients that are at high risk of developing infected chronic wounds. Calcium alginate dressings are indicated for the debridement during the inflammatory phase of healing. Since calcium ions are major activators of NK cells, we hypothesized that these dressings could enhance NK functions, as investigated in vitro herein. Primary human blood NK cells were freshly-isolated from healthy volunteers and exposed to conditioned media (CM) from two alginate dressings, Algosteril® (ALG, pure Ca2+ alginate) and Biatain® Alginate (BIA, Ca2+ alginate with CMC), in comparison with an exogenous 3mM calcium solution. Our results demonstrated that exogenous calcium and ALG-CM, but not BIA-CM, induced NK cell activation and enhanced their capacity to kill their targets as a result of increased degranulation. NK cell stimulation by ALG depended on the influx of extracellular Ca2+ via the SOCE Ca2+ permeable plasma membrane channels. ALG-CM also activated NK cell cytokine production of IFN-γ and TNF-α through a partly Ca2+-independent mechanism. This work highlights the non-equivalence between alginate dressings for NK cell stimulation and shows that the pure calcium alginate dressing Algosteril® enhances NK cell cytotoxic and immuno-modulatory activities. Altogether, these results underline a specific property of this medical device in innate defense that is key for the cutaneous wound healing process.

Derivation and Preclinical Characterization of CYT-303, a Novel NKp46-NK Cell Engager Targeting GPC3.

Glypican-3 (GPC3) is an oncofetal antigen that is highly expressed in multiple solid tumors, including hepatocellular carcinoma, and is barely expressed in adult normal tissues except the placenta. NKp46 activation receptor is expressed in all-natural killer (NK) cells, including tumor-infiltrating NK cells. FLEX-NKTM is a platform for the production of tetravalent multifunctional antibody NK cell engagers (NKE). CYT-303 was designed using the FLEX-NK scaffold, incorporating a novel humanized NKp46 binder that does not induce NKp46 internalization and a humanized GPC3 binder that targets the membrane-proximal lobe to mediate NK cell-redirected killing of HCC tumors. CYT-303 shows sub-nanomolar binding affinities to both GPC3 and NKp46. CYT-303 was highly potent and effective in mediating NK cell-redirected cytotoxicity against multiple HCC tumor cell lines and tumor spheroids. More interestingly, it can reverse the dysfunction induced in NK cells following repeated rounds of serial killing of tumors. It also mediated antibody-dependent cellular phagocytosis (ADCP) and complement-dependent cytotoxicity against GPC3-expressing HCC tumors. In vivo, CYT-303 showed no toxicity or cytokine release in cynomolgus monkeys up to the highest dose (60 mg/kg), administered weekly by intravenous infusion for 28 days. These results demonstrate the potential of CYT-303 to be a safe and effective therapy against HCC.

Cannabinoids as Immune System Modulators: Cannabidiol Potential Therapeutic Approaches and Limitations.

Introduction: Cannabidiol (CBD) is the second most abundant Phytocannabinoid in Cannabis extracts. CBD has a binding affinity for several cannabinoid and cannabinoid-associated receptors. Epidiolex (oral CBD solution) has been lately licensed by the Food and Drug Administration (FDA) for the treatment of pediatric epileptic seizures. Methods: In this review, we discussed the most promising applications of CBD for chronic inflammatory conditions, namely CBD's anti-inflammatory effects during inflammatory bowel disease, coronavirus disease (antiviral effect), brain pathologies (neuroprotective and anti-inflammatory properties), as well as CBD immunomodulatory and antitumoral activities in the tumor microenvironment. Special focus was shed on the main therapeutic mechanisms of action of CBD, particularly in the control of the immune system and the endocannabinoid system. Results: Findings suggest that CBD is a potent immunomodulatory drug as it has manifested immunosuppressive properties in the context of sterile inflammation (e.g., inflammatory bowel disease, rheumatoid arthritis, and neurodegenerative diseases), and immunoprotective effects during viral infections (e.g. COVID-19) Similarly, CBD has exhibited a selective response toward cancer types by engaging different targets and signaling pathways. These results are in favor of the primary function of the endocannabinoid system which is homeostatic maintenance. Conclusion: The presented evidence suggests that the endocannabinoid system is a prominent target for the treatment of inflammatory and autoimmune diseases, rheumatoid diseases, viral infections, neurological and psychological pathologies, and cancer. Moreover, the antitumoral activities of CBD have been suggested to be potentially used in combination with chemo- or immunotherapy during cancer. However, clinical results are still lacking, which raises a challenge to apply translational cannabis research to the human immune system.

CD160 receptor in CLL: Current state and future avenues.

CD160 is a glycosylphosphatidylinositol (GPI)-anchored cell surface glycoprotein expressed on cytotoxic natural killer (NK) cells and T-cell subsets. It plays a crucial role in the activation of NK-cell cytotoxicity and cytokine production. It also modulates the immune system and is involved in some pathologies, such as cancer. CD160 is abnormally expressed in B-cell chronic lymphocytic leukemia (CLL) but not expressed in normal B lymphocytes. Its expression in CLL enhances tumor cell proliferation and resistance to apoptosis. CD160 is also a potential prognostic marker for the detection of minimal residual disease (MRD) in CLL, which is important for the clinical management of CLL, the prevention of disease relapse, and the achievement of complete remission. In this review, we present an overview of CD160 and its involvement in the pathophysiology of CLL. We also discuss its use as a prognostic marker for the assessment of MRD in CLL.

Validation of AAC-11-Derived Peptide Anti-Tumor Activity in a Single Graft Sézary Patient-Derived Xenograft Mouse Model.

Sézary syndrome (SS) is an aggressive cutaneous T cell lymphoma with poor prognosis mainly characterized by the expansion of a tumor CD4+ T cell clone in both skin and blood. So far, the development of new therapeutic strategies has been hindered by a lack of reproducible in vivo models closely reflecting patients' clinical features. We developed an SS murine model consisting of the intravenous injection of Sézary patients' PBMC, together with a mixture of interleukins, in NOD-SCID-gamma mice. Thirty-four to fifty days after injection, mice showed skin disorders similar to that observed in patients, with the detection of epidermis thickening and dermal tumor T cell infiltrates. Although experimental variability was observed, Sézary cells could be tracked in the blood stream, confirming that our model could efficiently exhibit both skin and blood involvement. Using this model, we evaluated the therapeutic potential of RT39, a cell-penetrating peptide derived from the survival protein anti-apoptosis clone 11 (AAC-11), that we previously characterized as specifically inducing apoptosis of Sézary patients' malignant clone ex vivo. Systemic administration of RT39 led to cutaneous tumor T cells depletion, demonstrating efficient malignant cells' targeting and a favorable safety profile. These preclinical data confirmed that RT39 might be an innovative therapeutic tool for Sézary syndrome.

Cytotoxic activity of peripheral blood mononuclear cells in patients with endometriosis: A cross-sectional study.

Background: Endometriosis is believed to be associated with dysfunction of the lymphocyte population and cytotoxicity of natural killer (NK) cells, induced by the production of interleukin-2 (IL-2). Objective: This study aimed to investigate T lymphocytes and NK cell activity in the peripheral blood mononuclear cells (PBMCs) of women with endometriosis. Materials and Methods: PBMCs were obtained from the peripheral venous blood samples of 14 women with and without endometriosis (n = 7 for each group). Then, the PBMCs were co-cultured for 4 days and were treated with recombinant IL-2 for cytotoxic activity toward target cells (Daudi and K562 cells). The cytotoxicity activity was determined using the 51 chromium release assay before and after stimulation. Flow cytometry measurement was used to examine the expression of T lymphocytes and NK cells before and after being treated with IL-2. Results: The concentration of CD3+CD28+ (co-stimulatory) was significantly lower in the endometriosis group (65.62 ± 5.38) compared to in its counterpart (50.24 ± 4.22) (p = 0.04) before stimulation. However, no significant differences were observed in any other T lymphocytes and NK cells. It was also found that there was a significant increase of CD3-CD28+ after treatment with IL-2 only in the healthy control but not in women with endometriosis. Conclusion: Increased expression of CD160 and decreased CD28 play a role in inhibiting NK cell activation and T cell response in women with endometriosis.

Corrigendum: The NFAT3/RERG complex in luminal breast cancers is required to inhibit cell invasion and may be correlated with an absence of axillary lymph nodes colonization.

[This corrects the article DOI: 10.3389/fonc.2022.804868.].

The NFAT3/RERG Complex in Luminal Breast Cancers Is Required to Inhibit Cell Invasion and May Be Correlated With an Absence of Axillary Lymph Nodes Colonization.

Luminal breast cancers represent 70% of newly diagnosed breast cancers per annum and have a relatively good prognosis compared with triple-negative breast cancers. Luminal tumors that are responsive to hormonal therapy are particularly associated with a favorable prognosis. Nonetheless, the absolute number of metastatic relapses in luminal cancers is larger than in triple-negative breast cancers. A better understanding of the biology of luminal cancers, control of metastases formation, and identification of predictive markers of their evolution are therefore still necessary. In this context, we previously disclosed the key role of NFAT3 in regulating luminal breast cancer invasion. We have now identified a specific inhibitory region, in the C-terminal part of NFAT3, required for the inhibition of invasion of the human luminal breast cancer cell line T-47D. Indeed, we showed that this 85 amino acid C-terminal region acts as a dominant negative form of NFAT3 and that its overexpression in the T-47D cell line led to increased cell invasion. Mechanistically, we have revealed that this region of NFAT3 interacts with the small Ras GTPase RERG (RAS like estrogen regulated growth inhibitor) and shown that RERG expression is required for NFAT3 to impede T-47D cell invasion. We have validated the association of NFAT3 with RERG in human luminal breast cancer tissues. We have shown an increase of the quantity of the NFAT3/RERG complexes in patients without axillary lymph node colonization and therefore proposed that the detection of this complex may be a non-invasive marker of axillary lymph node colonization.

Cutaneous Wound Healing: A Review about Innate Immune Response and Current Therapeutic Applications.

Skin wounds and compromised wound healing are major concerns for the public. Although skin wound healing has been studied for decades, the molecular and cellular mechanisms behind the process are still not completely clear. The systemic responses to trauma involve the body's inflammatory and immunomodulatory cellular and humoral networks. Studies over the years provided essential insights into a complex and dynamic immunity during the cutaneous wound healing process. This review will focus on innate cell populations involved in the initial phase of this orchestrated process, including innate cells from both the skin and the immune system.