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NK cells are a major component of the antitumor immune response and are involved in controlling tumor progression and metastases in animal models. Here, we show that dysfunction of these cells accompanies human breast tumor progression. We characterized human peripheral blood NK (p-NK) cells and malignant mammary tumor-infiltrating NK (Ti-NK) cells from patients with noninvasive and invasive breast cancers. NK cells isolated from the peripheral blood of healthy donors and normal breast tissue were used as controls. With disease progression, we found that expression of activating NK cell receptors (such as NKp30, NKG2D, DNAM-1, and CD16) decreased while expression of inhibitory receptors (such as NKG2A) increased and that this correlated with decreased NK cell function, most notably cytotoxicity. Importantly, Ti-NK cells had more pronounced impairment of their cytotoxic potential than p-NK cells. We also identified several stroma-derived factors, including TGF-β1, involved in tumor-induced reduction of normal NK cell function. Our data therefore show that breast tumor progression involves NK cell dysfunction and that breast tumors model their environment to evade NK cell antitumor immunity. This highlights the importance of developing future therapies able to restore NK cell cytotoxicity to limit/prevent tumor escape from antitumor immunity.

BTLA (B- and T-lymphocyte attenuator) is a prominent co-receptor that is structurally and functionally related to CTLA-4 and PD-1. In T cells, BTLA inhibits TCR-mediated activation. In B cells, roles and functions of BTLA are still poorly understood and have never been studied in the context of B cells activated by CpG via TLR9. In this study, we evaluated the expression of BTLA depending on activation and differentiation of human B cell subsets in peripheral blood and lymph nodes. Stimulation with CpG upregulated BTLA, but not its ligand: herpes virus entry mediator (HVEM), on B cells in vitro and sustained its expression in vivo in melanoma patients after vaccination. Upon ligation with HVEM, BTLA inhibited CpG-mediated B cell functions (proliferation, cytokine production, and upregulation of co-stimulatory molecules), which was reversed by blocking BTLA/HVEM interactions. Interestingly, chemokine secretion (IL-8 and MIP1β) was not affected by BTLA/HVEM ligation, suggesting that BTLA-mediated inhibition is selective for some but not all B cell functions. We conclude that BTLA is an important immune checkpoint for B cells, as similarly known for T cells.

BackgroundCoronavirus disease 2019 (COVID-19) is a new pandemic disease caused by infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The C5a anaphylatoxin and its receptor C5aR1 (CD88) play a key role in the initiation and maintenance of several inflammatory responses, by recruiting and activating neutrophils and monocytes in the lungs.MethodsWe provide a longitudinal analysis of immune responses, including immune cell phenotyping and assessments of the soluble factors present in the blood and broncho-alveolar lavage fluid (BALF) of patients at various stages of COVID-19 severity: paucisymptomatic, pneumonia and acute respiratory distress syndrome (ARDS)ResultsWe report an increase in soluble C5a levels proportional to COVID-19 severity and high levels of C5aR1 expression in blood and pulmonary myeloid cells, supporting a role for the C5a-C5aR1 axis in the pathophysiology of ARDS. Avdoralimab, an anti-C5aR1 therapeutic monoclonal antibodies (mAbs) prevented C5a-mediated human myeloid cell recruitment and activation, and inhibited acute lung injury (ALI) in human C5aR1 knockin mice.ConclusionsThese results support the evaluation of avdoralimab to block C5a-C5aR1 axis as a mean of limiting myeloid cell infiltration in damaged organs and preventing the excessive lung inflammation and endothelialitis associated with ARDS in COVID-19 patientsAcknowledgementsThe Explore COVID-19 IPH group, the Explore COVID-19 Marseille Immunopole group.Ethics ApprovalHuman study protocol was approved by the Committee for the Protection of Persons Ile-de-France III – France (#2020-A00757-32). Animal experiments were approved by the ministere de l’enseignement superieur, de la recherche et de l’innovation – France (APAFIS#25418-2020051512242806 v2).

Coronavirus disease 2019 (COVID-19) is a disease caused by infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and has resulted in a pandemic 1 . The C5a complement factor and its receptor C5aR1 (also known as CD88) have a key role in the initiation and maintenance of several inflammatory responses by recruiting and activating neutrophils and monocytes 1 . Here we provide a longitudinal analysis of immune responses, including phenotypic analyses of immune cells and assessments of the soluble factors that are present in the blood and bronchoalveolar lavage fluid of patients at various stages of COVID-19 severity, including those who were paucisymptomatic or had pneumonia or acute respiratory distress syndrome. The levels of soluble C5a were increased in proportion to the severity of COVID-19 and high expression levels of C5aR1 receptors were found in blood and pulmonary myeloid cells, which supports a role for the C5a–C5aR1 axis in the pathophysiology of acute respiratory distress syndrome. Anti-C5aR1 therapeutic monoclonal antibodies prevented the C5a-mediated recruitment and activation of human myeloid cells, and inhibited acute lung injury in human C5aR1 knock-in mice. These results suggest that blockade of the C5a–C5aR1 axis could be used to limit the infiltration of myeloid cells in damaged organs and prevent the excessive lung inflammation and endothelialitis that are associated with acute respiratory distress syndrome in patients with COVID-19. Blockade of the C5a–C5aR1 axis using anti-C5aR1 monoclonal antibodies prevented inflammation associated with COVID-19.

Coronavirus disease 2019 (COVID-19) is a new pandemic acute respiratory disease caused by infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)11-3. We provide here a longitudinal analysis of immune responses, including immune cell phenotyping and assessments of the soluble factors present in the blood and broncho-alveolar lavage fluid (BALF) of patients at various stages of COVID-19 severity: paucisymptomatic, pneumonia and acute respiratory distress syndrome (ARDS). While we confirm a lymphopenia associated with COVID-19 severity4-7, we report an increase in expression of the NKG2A and PD-1 inhibitory receptors on T and natural killer (NK) cells, as well as an increase in CD39 expression on NK cells, suggesting that therapeutic blocking antibodies targeting these molecules already used for cancer immunotherapy8 could be repurposed as first line of defense to promote SARS-CoV-2 clearance. In addition, the C5a anaphylatoxin and its receptor C5aR1 (CD88) play a key role in the initiation and maintenance of inflammatory responses, by recruiting neutrophils and monocytes to the lungs9,10. We report an increase in soluble C5a levels proportional to COVID-19 severity and high levels of C5aR1 expression in blood and BALF myeloid cells, indicating a potential role of the C5a-C5aR1 axis in the pathophysiology of ARDS. Avdoralimab is a clinical-stage anti-C5aR1 therapeutic monoclonal antibody (mAb) that prevents C5a-mediated myeloid cell recruitment and activation. We propose the use of this antibody to limit myeloid cell infiltration in the lung and to prevent the excessive lung inflammation associated with ARDS in COVID-19 patients.