Acquired aplastic anemia:Is bystander insult to autologous hematopoiesis driven by immune surveillance against malignant cells?

We previously reported a serendipitous finding from a patient with refractory severe aplastic anemia who had gotten an unexpected hematological response to treatment with gut-cleansing preparations(GCPs).This patient experienced three recurrences over the ensuing one year of intermittent GCP treatments,with each recurrence occurring 7-8 wk from a GCP.After his third recurrence,he was prescribed successive treatment with rifampicin,berberine,and monthly administered GCP for 4 mo,and he developed an erythroid proliferative neoplasma and an overwhelming enteropathy,and eventually died of septic shock.Laboratory investigations had validated the resolution of myelosuppression and the appearance of malignant clonal hematopoiesis.From the treatment process and laboratory investigations,it is reasonably inferred that the engagement of gut inflammation is critically required in sustaining the overall pathophysiology of acquired aplastic anemia probably by creating a chronic inflammatory state.Incorporation of rifampicin,berberine,and monthly GCP into cyclosporine can enhance the immunosuppressive effect.In a subgroup of acquired aplastic anemia patients whose pathogenesis is associated with genotoxic exposure,the suppressed normal hematopoiesis may result from the bystander insult that is mediated by the soluble inflammatory cytokines generated in response to the immunogenic products of damaged hematopoietic cells in the context of chronic inflammatory state and may offer a protective antineoplastic mechanism against malignant proliferation.

Tumor microenvironment and immune surveillance

Tumor microenvironment(TME)comprises of tumor cells in vicinity of many additional cell types.Among many components of TME,immune cells represent a class of distinct cells that normally would be expected to suppress tumor growth and kill tumor cells,but are,instead,modulated by tumor cells to create conditions that support tumor growth,angiogenesis,metastasis and resistance against therapies.These immune cells include lymphocytes,natural killer cells,macrophages,dendritic cells,myeloid-derived suppressor cells and regulatory T-cells.Given the role these immune cells play in immune suppression within TME,it is important to clearly understand the mechanisms thereof so that the future immunotherapies can be tweaked and many of these immune cells could be reprogrammed to perform their normal cytotoxic/phagocytic activity for elimination of tumors.

Biochemical mechanisms implemented by human acute myeloid leukemia cells to suppress host immune surveillance

Acute myeloid leukaemia(AML)is a blood/bone marrow cancer originating from myeloid cell precusors capable of self-renewing.AML cells implement biochemical mechanisms which allow them not only to survive,but also to successfully escape immune surveillance.ln this work,we discuss crucial molecular mechanisms used by human AML cells in order to evade immune attack.

Adoptive immunotherapy for acute leukemia:New insights in chimeric antigen receptors

Relapses remain a major concern in acute leukemia. It is well known that leukemia stem cells(LSCs) hide in hematopoietic niches and escape to the immune system surveillance through the outgrowth of poorly immunogenic tumor-cell variants and the suppression of the active immune response. Despitethe introduction of new reagents and new therapeutic approaches, no treatment strategies have been able to definitively eradicate LSCs. However, recent adoptive immunotherapy in cancer is expected to revolutionize our way to fight against this disease, by redirecting the immune system in order to eliminate relapse issues. Initially described at the onset of the 90's, chimeric antigen receptors(CARs) are recombinant receptors transferred in various T cell subsets, providing specific antigens binding in a non-major histocompatibility complex restricted manner, and effective on a large variety of human leukocyte antigen-divers cell populations. Once transferred, engineered T cells act like an expanding "living drug" specifically targeting the tumor-associated antigen, and ensure long-term antitumor memory. Over the last decades, substantial improvements have been made in CARs design. CAR T cells have finally reached the clinical practice and first clinical trials have shown promising results. In acute lymphoblastic leukemia, high rate of complete and prolonged clinical responses have been observed after anti-CD19 CAR T cell therapy, with specific but manageable adverse events. In this review, our goal was to describe CAR structures and functions, and to summarize recent data regarding pre-clinical studies and clinical trials in acute leukemia.

Multiple characteristic alterations and available therapeutic strategies of cellular senescence

Given its state of stable proliferative inhibition,cellular senescence is primarily depicted as a critical mechanism by which organisms delay the progression of carcinogenesis.Cells undergoing senescence are often associated with the alteration of a series of specific features and functions,such as metabolic shifts,stemness induction,and microenvironment remodeling.However,recent research has revealed more complexity associated with senescence,including adverse effects on both physiological and pathological processes.How organisms evade these harmful consequences and survive has become an urgent research issue.Several therapeutic strategies targeting senescence,including senolytics,senomorphics,immunotherapy,and function restoration,have achieved initial success in certain scenarios.In this review,we describe in detail the characteristic changes associated with cellular senescence and summarize currently available countermeasures.