Summary
Despite major advances in recent years, immunosuppressive regimens for multiple sclerosis, rheumatoid arthritis, systemic lupus erythematosus and graft‐versus‐host disease still have major ...adverse effects and immunomodulation rather than immune paralysis would be desirable. Statins inhibit the rate‐limiting enzyme of the l‐mevalonate pathway, the 3‐hydroxy‐3‐methyl‐glutaryl‐coenzyme A reductase. It was shown that blocking the l‐mevalonate pathway reduces inflammation through effects on downstream metabolites of the pathway including farnesylpyrophosphates and geranylgeranylpyrophosphates, which are essential for the attachment of GTPases like RhoA, Rac and Ras to the cell membrane. Therefore, l‐mevalonate pathway downstream products play critical roles in the different steps of an immune response including immune cell activation, migration, cytokine production, immune metabolism and survival. This review discusses the relevance of the different metabolites for the immunomodulatory effect of statins and connects preclinical results with data from clinical studies that tested statins for the treatment of different inflammatory diseases.
Statins inhibit the rate limiting enzyme of the L‐mevalonate pathway. Thereby L‐mevalonate downstream products are reduced. As indicated certain downstream products are required for key steps during immune activation.
Inflammation is involved in tumor development and progression as well as antitumor response to therapy. In the past decade, the crosstalk between inflammation, immunity, and cancer has been ...investigated extensively, which led to the identification of several underlying mechanisms and cells involved. The formation of inflammasome complexes leads to the activation of caspase-1, production of interleukin (IL)-1β, and IL-18 and pyroptosis. Multiple studies have shown the involvement of NLRP3 inflammasome in tumorigenesis. Conversely, other reports have indicated a protective role in certain cancers. In this review, we summarize these contradictory roles of NLRP3 inflammasome in cancer, shed the light on oncogenic signaling leading to NLRP3 activation and IL-1β production and outline the current knowledge on therapeutic approaches.
Relapse of the original disease is a major cause of death after allogeneic hematopoietic cell transplantation for acute leukemias. There is growing evidence that relapses may be explained not only by ...resistance to chemotherapy but also by the escape of tumor cells from the control of the allogeneic immune response. Mechanisms of immune evasion can involve abrogation of leukemia cell recognition due to loss of HLA genes, immunosuppression by immune-checkpoint ligand expression, production of anti-inflammatory factors, release of metabolically active enzymes, loss of proinflammatory cytokine production, and acquisition of novel driver mutations that promote leukemia outgrowth. These mechanisms, and therapeutic targeting of immune escape, will be discussed. We divide the evidence in support of immune-escape mechanisms into animal studies, human laboratory studies, and human clinical experience. A better understanding of the molecular pathways connected to immune escape and relapse may help to improve our therapeutic armamentarium against acute myeloid leukemia relapse.
Acute graft-versus-host disease (GVHD) is a major life-threatening complication after allogeneic hematopoietic cell transplantation (allo-HCT). The classical target organs of acute GVHD include the ...intestines, liver, and skin. The damage of these organs is relatively easy to detect for the clinician as diarrhea, increased bilirubin, and rash. However, there is increasing evidence that other organs, where the acute damage is less apparent or more difficult to distinguish from drug toxicity, such as the central nervous system, lungs, ovaries and testis, thymus, bone marrow, and kidney, can be target organs of acute GVHD. Here, we review current evidence for nonclassical manifestations of acute GVHD in rodent models and in patients and discuss them in the context of novel emerging therapies for GVHD. A better understanding of the involvement of nonclassical GVHD target organs may help to improve patient outcomes after allo-HCT.
Abstract
Oncogenic
KRAS
mutations are the most frequent mutations in human cancer, but most difficult to target. While sustained proliferation caused by oncogenic
KRAS
-downstream signalling is a ...main driver of carcinogenesis, there is increasing evidence that it also mediates autocrine effects and crosstalk with the tumour microenvironment (TME). Here, we discuss recent reports connecting
KRAS
mutations with tumour-promoting inflammation and immune modulation caused by KRAS that leads to immune escape in the TME. We discuss the preclinical work on KRAS-induced inflammation and immune modulation in the context of currently ongoing clinical trials targeting cancer entities that carry
KRAS
mutations and strategies to overcome the oncogene-induced effects on the immune system.
Chronic graft-versus-host disease (cGVHD) is a major immunologic complication of allogeneic hematopoietic cell transplantation. cGVHD involves multiple organs, reduces quality of life, and often ...requires prolonged therapy with glucocorticoids, causing severe side effects. After 4 decades of testing multiple therapeutic approaches, ibrutinib, belumosudil, and ruxolitinib were US Food and Drug Administration approved for cGVHD in the last 4 years. Here we put a spotlight on their mechanisms of action, studies that led to approval, and their future role in cGVHD.
Treatment with immune checkpoint inhibitors targeting programmed death receptor-1 (PD-1) or programmed death ligand-1 (PD-L1) is effective in many cancer types. Tumors harboring specific mutations ...modulate antitumor immune responses through the PD-1/PD-L1 axis, and this should be taken into account when designing rational combinatory treatments.
Under normal conditions our intestines are inhabited by trillions of diverse microorganisms composing the intestinal microbiota, which are mostly non-pathogenic anaerobic commensal bacteria vital for ...the maintenance of immune homeostasis. The composition and diversity of the intestinal microbiota can be disturbed by various factors including diet, antibiotics, and exposure to intestinal pathogens. Alterations of the intestinal microbiota contributes to many diseases including graft-vs.-host disease (GVHD), a life threatening complication that occurs after allogeneic hematopoietic cell transplantation (allo-HCT) caused by an allogeneic reaction of donor T cells against recipient target tissues. Intestinal GVHD is most difficult to treat and connected to a high mortality. Due to recent advances in high-throughput sequencing technology, composition of the microbiome during allo-HCT has been characterized, and some common patterns have been identified. Metabolites produced by intestinal bacteria were shown to promote intestinal tissue homeostasis and immune tolerance post-allo-HCT. In this review, we discuss the role of the intestinal microbiota and metabolites in the context of acute GVHD. Moreover, novel therapeutic approaches that aim at protecting or regenerating intestinal cell populations will be highlighted.
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