Abstract
Inborn Errors of Immunity (IEI) comprise more than 450 inherited diseases, from which selected patients manifest a frequent and early incidence of malignancies, mainly lymphoma and leukemia. Primary antibody deficiency (PAD) is the most common form of IEI with the highest proportion of malignant cases. In this review, we aimed to compare the oncologic hallmarks and the molecular defects underlying PAD with other IEI entities to dissect the impact of avoiding immune destruction, genome instability, and mutation, enabling replicative immortality, tumor-promoting inflammation, resisting cell death, sustaining proliferative signaling, evading growth suppressors, deregulating cellular energetics, inducing angiogenesis, and activating invasion and metastasis in these groups of patients. Moreover, some of the most promising approaches that could be clinically tested in both PAD and IEI patients were discussed.
Highlights
Inborn Errors of Immunity (IEI), formerly known as primary immunodeficiencies, comprise at least 450 inherited diseases, from which selected patients manifest a frequent and early incidence of malignancies [1,2,3]
A proportion of patients with diseases of immune dysregulation show an increased susceptibility to herpes virus infections, which resulted from defects in co-stimulatory molecules essential for CD8+ memory T-cell formation (e.g., CD27 and CD70 deficiencies and OX40 deficiency associated with higher risk of lymphoma and sarcoma) [18,19,20,21]
Activation-induced cytidine deaminase (AICDA) and uracil DNA glycosylase (UNG) deficiencies affect the Class switch recombination (CSR) in B cells, presenting as a Primary antibody deficiency (PAD) known as hyper IgM syndrome with an increased incidence of hematologic cancers [38, 39]
Summary
Inborn Errors of Immunity (IEI), formerly known as primary immunodeficiencies, comprise at least 450 inherited diseases, from which selected patients manifest a frequent and early incidence of malignancies [1,2,3]. The longer the inflammation persists due to inadequate or inappropriate treatments, the higher the risk of associated tumorigenesis and the survival advantage of a cancerous cell [4]. From an oncologic point of view, the main hallmarks of cancer have recently been suggested to dissect the complexity of neoplastic disease [7]. The presented review compares oncologic hallmarks and the molecular defects underlying primary antibody deficiencies (PADs) with other IEI-associated cancers. The current published literature collection highlights that PAD patients have more diverse hallmarks of cancers. IEI and Cancer Hallmarks compared to other IEIs (except combined immunodeficiency and immune dysregulation) and have a higher number of cases with heterogeneous genetic defects or unknown molecular etiologies. Several therapeutic options are currently available for these diverse pathogeneses in PAD patients with cancer susceptibility, which should be considered by clinical immunologists and treating physicians
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