Much focus has been on the interaction of programmed cell death ligand 1 (PD-L1) on malignant B cells with programmed cell death 1 (PD-1) on effector T cells in inhibiting antilymphoma immunity. We sought to establish the contribution of natural killer (NK) cells and inhibitory CD163 monocytes/macrophages in Hodgkin lymphoma (cHL) and diffuse large B-cell lymphoma (DLBCL). Levels of PD-1 on NK cells were elevated in cHL relative to DLBCL. Notably, CD3CD56CD16 NK cells had substantially higher PD-1 expression relative to CD3CD56CD16 cells and were expanded in blood and tissue, more marked in patients with cHL than patients with DLBCL. There was also a raised population of PD-L1-expressing CD163 monocytes that was more marked in patients with cHL compared with patients with DLBCL. The phenotype of NK cells and monocytes reverted back to normal once therapy (ABVD [doxorubicin 25 mg/m, bleomycin 10 000 IU/m, vinblastine 6 mg/m, dacarbazine 375 mg/m, all given days 1 and 15, repeated every 28 days] or R-CHOP [rituximab 375 mg/m, cyclophosphamide 750 mg/m IV, doxorubicin 50 mg/m IV, vincristine 1.4 mg/m (2 mg maximum) IV, prednisone 100 mg/day by mouth days 1-5, pegfilgrastim 6 mg subcutaneously day 4, on a 14-day cycle]) had commenced. Tumor-associated macrophages (TAMs) expressed high levels of PD-L1/PD-L2 within diseased lymph nodes. Consistent with this, CD163/PD-L1/PD-L2 gene expression was also elevated in cHL relative to DLBCL tissues. An in vitro functional model of TAM-like monocytes suppressed activation of PD-1 NK cells, which was reversed by PD-1 blockade. In line with these findings, depletion of circulating monocytes from the blood of pretherapy patients with cHL and patients with DLBCL enhanced CD3CD56CD16 NK-cell activation. We describe a hitherto unrecognized immune evasion strategy mediated via skewing toward an exhausted PD-1-enriched CD3CD56CD16 NK-cell phenotype. In addition to direct inhibition of NK cells by the malignant B cell, suppression of NK cells can occur indirectly by PD-L1/PD-L2-expressing TAMs. The mechanism is more prominent in cHL than DLBCL, which may contribute to the clinical sensitivity of cHL to PD-1 blockade.

SUMMARY:Coagulation involves the regulated sequence of proteolytic activation of a series of zymogens to achieve appropriate and timely haemostasis in an injured vessel, in an environment that overwhelmingly favours an anticoagulant state. In the non-pathological state, the inciting event involves exposure of circulating factor VII/VIIa to extravascularly expressed tissue factor, which brings into motion the series of steps which results in amplification of the initial stimulus, culminating in the conversion of fibrinogen to fibrin and clot formation. The precisely synchronized cascade of events is counter-balanced by a system of anticoagulant mechanisms, which serve to ensure that the haemostatic effect is regulated and does not extend inappropriately. Conversely, in pathological states, these events can escape normal control mechanisms, due to either inherited or acquired defects, which lead to thrombosis. Current anticoagulant therapy, although based on medications that have been in existence for upwards of 80 years, is moving towards targeted therapy for specific coagulation factors and events in the coagulation cascade, based on the current knowledge of the main triggers and key events within the series of reactions that culminates in haemostasis. It remains to be seen whether these newer medications will become first-line therapies for thrombosis in the coming decade. This review aims to elucidate the main events within the coagulation cascade as it is currently understood to operate in vivo, with a brief discussion focusing on hypercoagulable states, and also a short review of the history of anticoagulants as they relate to this model.n ep_1228 462..470

Severe neutropenia associated with clozapine is a rare event and occurs early with a substantial decline in risk after one year of exposure. Death from clozapine-associated neutropenia is extremely rare. Implications for haematological monitoring are discussed.

Blockade of the PD-1 axis has modest efficacy in diffuse large B-cell lymphoma (DLBCL), but data regarding LAG3 are sparse. The impact of LAG3 digital gene expression was tested in 309 patients with DLBCL treated with standard chemoimmunotherapy. Cellular distribution of LAG3 protein was determined by immunohistochemistry and flow cytometry. In tumor-infiltrating lymphocytes (TILs), LAG3 expression was highest on CD4+ regulatory T cells (Tregs) and was also highly expressed on CD8+ T cells compared with CD4+ non-Tregs (both P = .008). LAG3high TILs were enriched in PD-1 and TIM-3. LAG3 was also expressed on a proportion of malignant B cells, and these patients had significantly higher LAG3 messenger RNA in their biopsies (P = .03). LAG3high gene expression was associated with inferior survival in discovery/validation cohorts, independent of cell of origin and the international prognostic index. Patients who were PD-L1high were fivefold more likely to be LAG3high (P < .0001). Patients who were LAG3high/PD-L1high had an inferior progression-free survival (P = .011) and overall survival (P = .005) compared with patients who were LAG3low/PD-L1high. Digital spatial protein analysis confirms LAG3 expression on T cells and, surprisingly, tumor-associated macrophages (TAMs) at higher levels than found on CD20+ B cells in the tumor microenvironment. LAG3 is frequently expressed on CD4+ Tregs and CD8+ TILs, typically with other immune checkpoints, and is also present in a proportion of malignant B cells in DLBCL and in areas enriched for TAMs. LAG3high expression is associated with poor outcome independent of conventional prognosticators.