Summary
Chemotherapy plus rituximab has been the mainstay of treatment for follicular lymphoma (FL) for two decades but is associated with immunosuppression and relapse. In phase 2 studies, ...lenalidomide combined with rituximab (R2) has shown clinical synergy in front‐line and relapsed/refractory FL. Here, we show that lenalidomide reactivated dysfunctional T and Natural Killer (NK) cells ex vivo from FL patients by enhancing proliferative capacity and T‐helper cell type 1 (Th1) cytokine release. In combination with rituximab, lenalidomide improved antibody‐dependent cellular cytotoxicity in sensitive and chemo‐resistant FL cells, via a cereblon‐dependent mechanism. While single‐agent lenalidomide and rituximab increased formation of lytic NK cell immunological synapses with primary FL tumour cells, the combination was superior and correlated with enhanced cytotoxicity. Immunophenotyping of FL patient samples from a phase 3 trial revealed that R2 treatment increased circulating T‐ and NK‐cell counts, while R‐chemotherapy was associated with reduced cell numbers. Finally, using an in vitro model of myeloid differentiation, we demonstrated that lenalidomide caused a reversible arrest in neutrophil maturation that was distinct from a cytotoxic chemotherapeutic agent, which may help explain the lower rates of neutropenia observed with R2 versus R‐chemotherapy. Taken together, we believe these data support a paradigm shift in the treatment of FL – moving from combination immunochemotherapy to chemotherapy‐free immunotherapy.
Keywords: AL amyloidosis; cardiac amyloidosis; venetoclax; BH3 mimetics; apoptosis CAPTION(S): Table SI. Haematological, cardiac, and renal response in evaluable patients treated with venetoclax. ...ORR, overall response rate; CR, complete response; VGPR, very good partial response PR, partial response; SD stable disease; PD, progressive disease. Table SII. Adverse events reported during treatment with venetoclax, as recorded according to the Common Terminology Criteria for Adverse Events version v5.0. Fig S1. Overall survival, estimated by Kaplan Meier curve, from the time of venetoclax initiation to death. Byline: Helene Pasquer, Karim Belhadj, Jehan Dupuis, Sylvia Oghina, Antoine Galat, Amandine Ladaique, Alizee Maarek, Louise Roulin, Romain Gounot, Elsa Poulot, Asma Beldi-Ferchiou, Valerie Molinier-Frenkel, Corinne Haioun, Thibaud Damy, Fabien Le Bras, Francois Lemonnier
Summary
Low baseline NK‐cell counts (NKCCs) in patients with diffuse large B‐cell lymphoma (DLBCL) are associated with a poor prognosis. The REMARC phase III trial (NCT01122472) showed that ...lenalidomide maintenance prolonged PFS in rituximab–chemotherapy responders. We conducted a REMARC ancillary study analysing the impact of lenalidomide maintenance on the prognostic value of low NKCCs. Blood samples from 335 elderly French patients enrolled in the REMARC trial were analysed by flow cytometry to obtain NKCCs at diagnosis (n = 220), at randomization (n = 186) and/or six months after randomization (n = 184). Baseline NKCCs < 100 cells/μl were associated with shorter PFS and OS (HRs = 2.2 (1.4, 3.3), p < 0.001 and 2.8 (1.7, 4.5), p < 0.001, respectively), independently of aaIPI. In a competing risk analysis, low NKCCs at baseline were associated with a higher risk of relapse/progression (p = 0.0025), but not of death without progression (p = 0.33). Lenalidomide did not affect the prognosis value of low baseline NKCCs (p = 0.6349). Similar results were obtained for low NKCCs at randomization. Our results demonstrate that low NKCCs at baseline and post rituximab–chemotherapy are robust prognostic factors in DLBCL and reveal that lenalidomide has no impact on this parameter. Other therapeutic strategies aiming at improving NK‐cell function could improve outcomes in DLBCL.
The development of cancer and chronic infections is facilitated by many subversion mechanisms, among which enhanced expression of immune checkpoints molecules, such as programmed death-1 (PD-1) and ...cytotoxic T lymphocyte-associated antigen 4 (CTLA-4), on exhausted T cells. Recently, immune checkpoint inhibitors have shown remarkable efficiency in the treatment of a number of cancers. However, expression of immune checkpoints on natural killer (NK) cells and its functional consequences on NK cell effector functions are much less explored. In this review, we focus on the current knowledge on expression of various immune checkpoints in NK cells, how it can alter NK cell-mediated cytotoxicity and cytokine production. Dissecting the role of these inhibitory mechanisms in NK cells is critical for the full understanding of the mode of action of immunotherapies using checkpoint inhibitors in the treatment of cancers and chronic infections.
Memory B cells play a fundamental role in host defenses against viruses, but to date, their role has been relatively unsettled in the context of SARS-CoV-2. We report here a longitudinal single-cell ...and repertoire profiling of the B cell response up to 6 months in mild and severe COVID-19 patients. Distinct SARS-CoV-2 spike-specific activated B cell clones fueled an early antibody-secreting cell burst as well as a durable synchronous germinal center response. While highly mutated memory B cells, including pre-existing cross-reactive seasonal Betacoronavirus-specific clones, were recruited early in the response, neutralizing SARS-CoV-2 RBD-specific clones accumulated with time and largely contributed to the late, remarkably stable, memory B cell pool. Highlighting germinal center maturation, these cells displayed clear accumulation of somatic mutations in their variable region genes over time. Overall, these findings demonstrate that an antigen-driven activation persisted and matured up to 6 months after SARS-CoV-2 infection and may provide long-term protection.
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•Seasonal coronavirus memory B cells contribute to the early anti-SARS-CoV-2 response•Spike-specific memory B cells with a resting phenotype increase up to 6 months•Somatic mutations accumulate in SARS-CoV-2-specific memory B cells over time•Longitudinal study reveals a temporal switch to anti-RBD neutralizing memory B cells
The B cell response against SARS-CoV-2 shows a temporal shift from an extrafollicular reaction that includes memory B cells against seasonal coronaviruses toward a germinal center-dependent memory response encoding (spike-specific) neutralizing antibodies.
Biomarkers of disease severity might help individualizing the management of patients with the acute respiratory distress syndrome (ARDS). Whether the alveolar compartmentalization of biomarkers has a ...clinical significance in patients with pneumonia-related ARDS is unknown. This study aimed at assessing the interrelation of ARDS/sepsis biomarkers in the alveolar and blood compartments and explored their association with clinical outcomes.
Immunocompetent patients with pneumonia-related ARDS admitted between 2014 and 2018 were included in a prospective monocentric study. Bronchoalveolar lavage (BAL) fluid and blood samples were obtained within 48 h of admission. Twenty-two biomarkers were quantified in BAL fluid and serum. HLA-DR
monocytes and CD8
PD-1
lymphocytes were quantified using flow cytometry. The primary clinical endpoint of the study was hospital mortality. Patients undergoing a bronchoscopy as part of routine care were included as controls.
Seventy ARDS patients were included. Hospital mortality was 21.4%. The BAL fluid-to-serum ratio of IL-8 was 20 times higher in ARDS patients than in controls (p < 0.0001). ARDS patients with shock had lower BAL fluid-to-serum ratio of IL-1Ra (p = 0.026), IL-6 (p = 0.002), IP-10/CXCL10 (p = 0.024) and IL-10 (p = 0.023) than others. The BAL fluid-to-serum ratio of IL-1Ra was more elevated in hospital survivors than decedents (p = 0.006), even after adjusting for SOFA and driving pressure (p = 0.036). There was no significant association between alveolar or alveolar/blood monocytic HLA-DR or CD8
lymphocytes PD-1 expression and hospital mortality.
IL-8 was the most compartmentalized cytokine and lower BAL fluid-to-serum concentration ratios of IL-1Ra were associated with hospital mortality in patients with pneumonia-associated ARDS.
Sustained activation of JAK/STAT3 signaling pathway is classically described in Multiple Myeloma (MM). One explanation could be the silencing of the JAK/STAT suppressor genes, through the ...hypermethylation of SHP-1 and SOCS-1, previously demonstrated in MM cell lines or in whole bone marrow aspirates. The link between such suppressor gene silencing and the degree of bone marrow invasion or the treatment response has not been evaluated in depth. Using real-time RT-PCR, we studied the expression profile of three JAK/STAT suppressor genes: SHP-1, SHP-2 and SOCS-1 in plasma cells freshly isolated from the bone marrows of MM patients and healthy controls. Our data demonstrated an abnormal repression of such genes in malignant plasma cells and revealed a significant correlation between such defects and the sustained activation of the JAK/STAT3 pathway during MM. The repressed expression of SHP-1 and SHP-2 correlated significantly with a high initial degree of bone marrow infiltration but was, unexpectedly, associated with a better response to the induction therapy. Collectively, our data provide new evidences that substantiate the contribution of JAK/STAT suppressor genes in the pathogenesis of MM. They also highlight the possibility that the decreased gene expression of SHP-1 and SHP-2 could be of interest as a new predictive factor of a favorable treatment response, and suggest new potential mechanisms of action of the therapeutic molecules. Whether such defect helps the progression of the disease from monoclonal gammopathy of unknown significance to MM remains, however, to be determined.
Outcomes for follicular lymphoma (FL) have greatly improved, but most patients will ultimately relapse. High total metabolic tumor volume (TMTV), computed from baseline ...18F-fluorodeoxyglucose–positron emission tomography (PET), is associated with shorter progression-free survival (PFS), but circulating tumor cells (CTCs) and cell-free DNA (cfDNA) may also reflect tumor burden and be of prognostic value. The aim of our study was to correlate CTCs and cfDNA with TMTV in FL at diagnosis and to determine their prognostic values. We retrospectively analyzed 133 patients (with previously untreated FL and a baseline PET) from 2 cohorts with either a baseline plasma sample (n = 61) or a bcl2-JH-informative peripheral blood (PB) sample (n = 68). Quantification of circulating bcl2-JH+ cells and cfDNA was performed by droplet digital polymerase chain reaction. A significant correlation was found between TMTV and both CTCs (P < .0001) and cfDNA (P < .0001). With a median 48-month follow-up, 4-year PFS was lower in patients with TMTV > 510 cm3 (P = .0004), CTCs >0.0018 PB cells (P = .03), or cfDNA >2550 equivalent-genome/mL (P = .04). In comparison with TMTV alone, no additional prognostic information was obtained by measuring CTCs. In contrast, Cox multivariate analysis, including cfDNA and TMTV, showed that both cfDNA and TMTV remained predictive of outcome. In conclusion, CTCs and cfDNA correlate with TMTV in FL, and all 3 influence patient outcome. PFS was shorter for patients with high cfDNA and TMTV, suggesting that these parameters provide relevant information for tumor-tailored therapy.
•Cell-free DNA and circulating tumor cells are related to TMTV in follicular lymphoma at diagnosis.•Cell-free DNA levels, in addition to TMTV, define high-risk follicular lymphoma patients.
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The induction of specific and sustainable tolerance is a challenging issue in organ transplantation. The discovery of the immunosuppressive properties of apoptotic cells in animal models has paved ...the way for their use in human transplantation. In this work, we aimed to define a stable, reproducible, and clinically compatible production procedure of human apoptotic cells (Apo-cells). Using a clinically approved extracorporeal photopheresis technique, we have produced and characterized phenotypically and functionally human apoptotic cells. These Apo-cells have immunosuppressive properties proved
and
in NOD/SCID/γC mice by their capacity to modulate an allogeneic response following both a direct and an indirect antigen presentation. These results brought the rationale for the use of Apo-cells in tolerance induction protocol for organ transplantation.
BackgroundTargeting immune checkpoints that inhibit antitumor immune responses has emerged as a powerful new approach to treat cancer. We recently showed that blocking the tumor necrosis factor ...receptor-type 2 (TNFR2) pathway induces the complete loss of the protective function of regulatory T cells (Tregs) in a model of graft-versus-host disease (GVHD) prevention that relies on Treg-based cell therapy. Here, we tested the possibility of amplifying the antitumor response by targeting TNFR2 in a model of tumor relapse following hematopoietic stem-cell transplantation, a clinical situation for which the need for efficient therapeutic options is still unmet.MethodWe developed appropriate experimental conditions that mimic patients that relapsed from their initial hematological malignancy after hematopoietic stem-cell transplantation. This consisted of defining in allogeneic bone marrow transplantation models developed in mice, the maximum number of required tumor cells and T cells to infuse into recipient mice to develop a model of tumor relapse without inducing GVHD. We next evaluated whether anti-TNFR2 treatment could trigger alloreactivity and consequently antitumor immune response. In parallel, we also studied the differential expression of TNFR2 on T cells including Treg from patients in post-transplant leukemia relapse and in patients developing GVHD.ResultsUsing experimental conditions in which neither donor T cells nor TNFR2-blocking antibody per se have any effect on tumor relapse, we observed that the coadministration of a suboptimal number of T cells and an anti-TNFR2 treatment can trigger alloreactivity and subsequently induce a significant antitumor effect. This was associated with a reduced percentage of activated CD4+ and CD8+ Tregs. Importantly, human Tregs over-expressed TNFR2 relative to conventional T cells in healthy donors and in patients experiencing leukemia relapse or cortico-resistant GVHD after hematopoietic stem cell transplantation.ConclusionsThese results highlight TNFR2 as a new target molecule for the development of immunotherapies to treat blood malignancy relapse, used either directly in grafted patients or to enhance donor lymphocyte infusion strategies. More widely, they open the door for new perspectives to amplify antitumor responses against solid cancers by directly targeting Tregs through their TNFR2 expression.
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