Reverting immune suppression to enhance cancer immunotherapy

Tumors employ strategies to escape immune control. The principle aim of most cancer immunotherapies is to restore effective immune surveillance. Among the different processes regulating immune escape, tumor microenvironment-associated soluble factors, and/or cell surface-bound molecules are mostly responsible for dysfunctional activity of tumor-specific CD8+T cells. These dynamic immunosuppressive networks prevent tumor rejection at several levels, limiting also the success of immunotherapies. Nevertheless, the recent clinical development of immune checkpoint inhibitors or of molecules modulating cellular targets and immunosuppressive enzymes highlights the great potential of approaches based on the selective disruption of immunosuppressive networks. Currently, the administration of different categories of immunotherapy in combination regimens is the ultimate modality for impacting the survival of cancer patients. With the advent of immune checkpoint inhibitors, designed to mount an effective antitumor immune response, profound changes occurred in cancer immunotherapy: from a global stimulation of the immune system to a specific targeting of an immune component. This review will specifically highlight the players, the mechanisms limiting an efficient antitumor response and the current immunotherapy modalities tailored to target immune suppressive pathways. We also discuss the ongoing challenges encountered by these strategies and provide suggestions for circumventing hurdles to new immunotherapeutic approaches, including the use of relevant biomarkers in the optimization of immunotherapy regimens and the identification of patients who can benefit from defined immune-based approaches

Granulocyte transfusions in children and adults with hematological malignancies: benefits and controversies

Bacterial and fungal infections continue to pose a major clinical challenge in patients with prolonged severe neutropenia after chemotherapy or hematopoietic stem cell transplantation (HSCT). With the advent of granulocyte colony-stimulating factor (G-CSF) to mobilize neutrophils in healthy donors, granulocyte transfusions have been broadly used to prevent and/or treat life-threatening infections in patients with severe febrile neutropenia and/or neutrophil dysfunction. Although the results of randomized controlled trials are inconclusive, there are suggestions from pilot and retrospective studies that granulocyte transfusions may benefit selected categories of patients. We will critically appraise the evidence related to the use of therapeutic granulocyte transfusions in children and adults, highlighting current controversies in the field and discussing complementary approaches to modulate phagocyte function in the host

Cytokine and Chemokine Profile in Amicrobial Pustulosis of the Folds: Evidence for Autoinflammation

Autoinflammation has recently been suggested in the pathogenesis of neutrophilic dermatoses but systematic studies on their cytokine profile are lacking. Notably, amicrobial pustulosis of the folds (APF), classified among neutrophilic dermatoses, has been studied only in small case series.In our University Hospital, we conducted an observational study on 15 APF patients, analyzing their clinical and laboratory features with a follow-up of 9 months to 20 years. Skin cytokine pattern of 9 of them was compared to that of 6 normal controls.In all patients, primary lesions were pustules symmetrically involving the skin folds and anogenital region with a chronic-relapsing course and responding to corticosteroids. Dapsone, cyclosporine, and tumor necrosis factor blockers were effective in refractory cases. In skin samples, the expressions of interleukin (IL)-1\u3b2, pivotal cytokine in autoinflammation, and its receptors I and II were significantly higher in APF (P\u200a=\u200a0.005, 0.018, and 0.034, respectively) than in controls. Chemokines responsible for neutrophil recruitment such as IL-8 (P\u200a=\u200a0.003), CXCL 1/2/3 (C-X-C motif ligand 1/2/3) (P\u200a=\u200a0.010), CXCL 16 (P\u200a=\u200a0.045), and RANTES (regulated on activation, normal T cell expressed and secreted) (P\u200a=\u200a0.034) were overexpressed. Molecules involved in tissue damage like matrix metalloproteinase-2 (MMP-2) (P\u200a=\u200a0.010) and MMP-9 (P\u200a=\u200a0.003) were increased.APF is a pustular neutrophilic dermatosis with a typical distribution in all patients. The disorder may coexist with an underlying autoimmune/dysimmune disease but is often associated only with a few autoantibodies without a clear autoimmunity. The overexpression of cytokines/chemokines and molecules amplifying the inflammatory network supports the view that APF has an important autoinflammatory component

Paradoxical Autoinflammatory Skin Reaction to Tumor Necrosis Factor Alpha Blockers Manifesting as Amicrobial Pustulosis of the Folds in Patients With Inflammatory Bowel Diseases

The therapy of inflammatory bowel disease, particularly with tumor necrosis factor (TNF) blockers, may be associated with a number of cutaneous adverse effects, including psoriasis-like, eczema-like, and lichenoid eruptions. Other rare skin complications are neutrophilic dermatoses such as amicrobial pustulosis of the folds (APF), which is a chronic relapsing pustular disorder classified in this spectrum.The authors analyzed clinical, histopathologic, and cytokine expression profiles of 3 inflammatory bowel disease patients with APF triggered by adalimumab (patient 1) and infliximab (patients 2 and 3).All 3 patients presented with sterile pustules involving the cutaneous folds, genital regions, and scalp 6 months after starting adalimumab (patient 1) and 9 months after starting infliximab (patients 2 and 3). Histology was characterized by epidermal spongiform pustules with a dermal neutrophilic and lymphocytic infiltrate. Tumor necrosis factor blocker withdrawal associated with topical and systemic corticosteroids induced complete remission of APF in all 3 patients. The expressions of interleukin (IL)-1 beta and its receptors as well as TNF alpha and its receptors were significantly higher in APF than in controls. Also IL-17, leukocyte selectin, and chemokines, such as IL-8, [C-X-C motif] chemokine ligand 1/2/3 (C\u200a=\u200acysteine, X\u200a=\u200aany amino acid), [C-X-C motif] chemokine ligand 16 (C\u200a=\u200acysteine, X\u200a=\u200aany amino acid), and RANTES (regulated on activation, normal T cell expressed and secreted) were significantly overexpressed. Finally, the authors found significant overexpression of both metalloproteinases 2/9 and their inhibitors 1/2.The observation of 3 patients with APF following anti-TNF therapy expands not only the clinical context of APF but also the spectrum of anti-TNF side effects. Overexpression of cytokines/chemokines and molecules amplifying the inflammatory network supports the view that APF is autoinflammatory in origin

Lung Ultrasound Findings and Endothelial Perturbation in a COVID-19 Low-Intensity Care Unit

Hypercoagulability and endothelial dysfunction related to inflammation have been clearly demonstrated in COVID-19. However, their influence on thromboembolism, lung alterations and mortality in low-intensity-care patients with COVID-19 is not completely clarified. Our aims were to evaluate the prevalence of deep vein thrombosis (DVT) with compressive ultrasound (CUS); to describe lung ultrasound (LUS) features; and to study coagulation, inflammatory and endothelial perturbation biomarkers in COVID-19 patients at low-intensity care unit admission. The predictive value of these biomarkers on mortality, need for oxygen support and duration of hospitalization was also evaluated. Of the 65 patients included, 8 were non-survivors. CUS was negative for DVT in all patients. LUS Soldati and Vetrugno scores were strongly correlated (rho = 0.95) with each other, and both significantly differed in patients who needed oxygen therapy vs. those who did not (Soldati p = 0.017; Vetrugno p = 0.023), with coalescent B lines as the most prevalent pattern in patients with a worse prognosis. Mean (SD) levels of thrombomodulin and VCAM-1 were higher in non-survivors than in survivors (7283.9 pg/mL (3961.9 pg/mL) vs. 4800.7 pg/mL (1771.0 pg/mL), p = 0.004 and 2299 ng/mL (730.35 ng/mL) vs. 1451 ng/mL (456.2 ng/mL), p < 0.001, respectively). Finally, in a multivariate analysis model adjusted for age, sex and Charlson score, VCAM-1 level increase was independently associated with death [OR 1.31 (1.06, 1.81; p = 0.036)]. In conclusion, in a cohort of mild COVID-19 patients, we found no DVT events despite the highly abnormal inflammatory, endothelial and coagulation parameters. The presence of lung alterations at admission could not predict outcome. The endothelial perturbation biomarker VCAM-1 emerged as a promising prognostic tool for mortality in COVID-19

Attivazione della coagulazione nelle dermatosi bollose autoimmuni

Pemfigo volgare (PV) e pemfigoide bolloso (PB) sono dermatosi bollose di origine autoimmune che si differenziano principalmente per la sede di formazione delle bolle e per l\u2019intensit\ue0 del processo infiammatorio ad esse associato. Nel PV la bolla \ue8 infatti intraepidermica e consegue al danneggiamento delle giunzioni intercellulari dovuto al legame di autoanticorpi IgG con le desmogleine desmosomiali 3 e 1, mentre nel BP lo scollamento bolloso avviene a livello della giunzione dermoepidermica ed \ue8 causato da autoanticorpi diretti contro due antigeni emidesmosomiali, BP180 e BP 230. L\u2019infiltrato infiammatorio \ue8 denso e ricco in eosinofili nel BP e scarso nel PV. E\u2019 noto che l\u2019infiammazione attivi la cascata coagulatoria in diverse patologie. In questo studio abbiamo valutato l\u2019attivazione della coagulazione a livello sia locale che sistemico nel BP e nel PV. Sono stati studiati 20 pazienti affetti da BP (10 in fase attiva e 10 in remissione), 23 pazienti con PV (13 attivi e 10 in remissione) e 10 soggetti sani. Sono stati misurati due marcatori di attivazione della coagulazione, il frammento della protrombina F1+2 e il D-dimero, con metodiche ELISA nel plasma dei pazienti e dei controlli. L\u2019espressione del tissue factor (TF), il principale iniziatore della cascata coagulatoria, \ue8 stata valutata con metodica immunoistochimica su campioni cutanei di 10 pazienti con PV, 10 pazienti con BP attivo e sulla cute sana di 10 controlli. I livelli plasmatici di F1+2 e D-dimero erano elevati nei pazienti con BP attivo (P = 0\ub7001), mentre nel PV attivo i livelli di entrambi i parametri erano normali. In fase di remissione i livelli plasmatici di F1+2 e D-dimero erano normali sia nel BP che nel PV. E\u2019 stata dimostrata immunoreattivit\ue0 cutanea per TF nel BP attivo ma non nel PV attivo n\ue9 nella cute sana. Lo score di reattivit\ue0 del TF era pi\uf9 elevato nel BP attivo rispetto ai controlli sani e al PV attivo (P = 0\ub70001). Non vi erano differenze nello score di TF tra PV attivo e controlli. In conclusione, il BP si associa ad attivazione della coagulazione che invece \ue8 assente nel PV. I nostri dati forniscono una possibile spiegazione fisiopatologica dell\u2019aumentato rischio trombotico osservato nei pazienti con BP ma non in quelli con PV

Espressione di tissue factor da parte degli eosinofili in pazienti con orticaria cronica

Sebbene numerosi casi di orticaria cronica siano attualmente considerati di origine autoimmune e associati alla presenza di autoanticorpi circolanti che inducono il rilascio di istamina, vi sono chiare evidenze sul ruolo fisiopatologico dell\u2019attivazione della coagulazione mediata dal tissue factor (TF), il principale iniziatore della cascata coagulatoria. E\u2019 stato di recente dimostrato che gli eosinofili, peraltro presenti nella cute lesionale di pazienti con orticaria cronica, sono la maggiore fonte di TF nel sangue umano. In questo studio abbiamo valutato se gli eosinofili esprimano TF nella cute lesionale di pazienti con orticaria cronica. Abbiamo studiato 20 pazienti con orticaria cronica grave, prelevando campioni bioptici cutanei da lesioni pomfoidi attive. Come gruppo di controllo sono stati utilizzati campioni di cute sana perilesionale ottenuti dall\u2019escissione chirurgica di diversi tipi di tumori cutanei (10 casi) e varie patologie cutanee caratterizzate da infiltrati usualmente privi di eosinofili, quali vasculite leucocitoclasica (7 casi), lichen planus (8 casi) e mastocitosi (3 casi). L\u2019espressione del TF \ue8 stata valutata con metodica immunoistochimica utilizzando un anticorpo monoclonale anti-TF. Sono stati inoltre eseguiti esperimenti di colocalizzazione del TF con la proteina cationica eosinofila (ECP), considerata un marcatore classico degli eosinofili, con la tecnica del doppio marcaggio mediante due anticorpi monoclonali specifici. In tutti i campioni di cute dei pazienti con orticaria cronica \ue8 stata osservata un\u2019intensa espressione del TF che era invece assente nei controlli normali (P=0.0001) e nelle malattie cutanee non eosinofilo-mediate (P=0.001-0.0001). Le indagini di doppio marcaggio per TF e ECP hanno dimostrato che le cellule positive per TF erano eosinofili. In conclusione, gli eosinofili rappresentano la principale fonte di TF nella cute lesionale di pazienti con orticaria cronica. I nostri risultati enfatizzano il ruolo di queste cellule nella fisiopatologia dell\u2019orticaria cronica fornendo il razionale per nuove strategie terapeutiche

Paradoxical Skin Reactions to Biologics in Patients With Rheumatologic Disorders

Targeted immune-modulating treatment with biological agents has revolutionized the management of immune-mediated inflammatory diseases, including rheumatologic conditions. The efficacy and tolerability of biological agents, from the initial tumour necrosis factor (TNF)-\u3b1 inhibitors to the new anti-cytokine monoclonal antibodies, have dramatically changed the natural history of debilitating conditions such as rheumatoid arthritis and seronegative spondyloarthropathies. The widening use of biologics across several rheumatologic diseases has been associated with a new class of adverse events, the so-called paradoxical reactions. These events are inflammatory immune-mediated tissue reactions, developing paradoxically during treatment of rheumatologic conditions with targeted biologics that are commonly used for treating the idiopathic counterparts of these drug-induced reactions. The skin is frequently involved, and, even if considered rare to uncommon, these cutaneous manifestations are an important cause of biologic agent discontinuation. TNF-\u3b1 antagonist-induced psoriasis, which can manifest de novo or as exacerbation of a pre-existing form, is the prototypic and most frequent paradoxical skin reaction to biologics while other reactions, such as eczematous and lichenoid eruptions, hidradenitis suppurativa, pyoderma gangrenosum, Sweet's syndrome and granulomatous skin diseases, occur much more rarely. Management of these reactions consists of topical or systemic skin-directed therapies, depending on the severity and extension of the cutaneous picture, and it is generally associated with switching over to other disease-modifying regimens for treating the underlying rheumatologic condition. Here, we review in detail the current concepts and controversies on classification, pathogenesis and clinical management of this new class of cutaneous adverse events induced by biologics in rheumatologic patients