Primary Immunodeficiency and Cancer Predisposition Revisited: Embedding Two Closely Related Concepts Into an Integrative Conceptual Framework

Abstract

Common understanding suggests that the normal function of a “healthy” immune system safe-guards and protects against the development of malignancies, whereas a genetically impaired one might increase the likelihood of their manifestation. This view is primarily based on and apparently supported by an increased incidence of such diseases in patients with specific forms of immunodeficiencies that are caused by high penetrant gene defects. As I will review and discuss herein, such constellations merely represent the tip of an iceberg. The overall situation is by far more varied and complex, especially if one takes into account the growing difficulties to define what actually constitutes an immunodeficiency and what defines a cancer predisposition. The enormous advances in genome sequencing, in bioinformatic analyses and in the functional in vitro and in vivo assessment of novel findings together with the availability of large databases provide us with a wealth of information that steadily increases the number of sequence variants that concur with clinically more or less recognizable immunological problems and their consequences. Since many of the newly identified hard-core defects are exceedingly rare, their tumor predisposing effect is difficult to ascertain. The analyses of large data sets, on the other hand, continuously supply us with low penetrant variants that, at least in statistical terms, are clearly tumor predisposing, although their specific relevance for the respective carriers still needs to be carefully assessed on an individual basis. Finally, defects and variants that affect the same gene families and pathways in both a constitutional and somatic setting underscore the fact that immunodeficiencies and cancer predisposition can be viewed as two closely related errors of development. Depending on the particular genetic and/or environmental context as well as the respective stage of development, the same changes can have either a neutral, predisposing and, in some instances, even a protective effect. To understand the interaction between the immune system, be it “normal” or “deficient” and tumor predisposition and development on a systemic level, one therefore needs to focus on the structure and dynamic functional organization of the entire immune system rather than on its isolated individual components alone.

Biophysical and Epigenetic Regulation of Cancer Stemness, Invasiveness, and Immune Action

“…While active adaptive immunity can lead to favorable clinical outcomes based on effective malignancy clearance, chronic inflammatory responses of innate immune cells in the vicinity of precancerous tissue may lead to tumorigenesis. Likewise, immune insufficiency can also result in increased cancer susceptibility, as seen in cases of primary immunodeficiency diseases [79], organ transplant-associated drug-induced immunosuppression [80], absence of immune cells including natural killer (NK), natural killer T cells (NKT), gamma delta (γδ) T cells, and other lymphocytes, or deficiency of immune products such as interferon-gamma (IFN-γ), perforins, and GM-CSF [81][82][83][84]. In this section, we discuss how cancer-associated biophysical cues influence immune cell phenotype through altered transcriptional and epigenetic programs (outlined in Fig.…”

Serum Free Immunoglobulins Light Chains: A Common Feature of Common Variable Immunodeficiency?

“…The type of malignancy seems to be highly dependent on the specific PID, the age of the patient, and chronic infectious stimuli or dysbiosis involving complex pathogenic mechanisms (35). Cancer is 1.4 to 5-fold higher in registrybased PID studies respect to general population (36,37), from which 70% corresponds to lymphoid malignancy (38,39). Individuals with CVID are at 5 to 10-fold higher risk of developing hematological malignancies (36,37,40), while unexpectedly lower incidence on most common cancers than general population has been described (41,42).…”

“…Cancer is 1.4 to 5-fold higher in registrybased PID studies respect to general population (36,37), from which 70% corresponds to lymphoid malignancy (38,39). Individuals with CVID are at 5 to 10-fold higher risk of developing hematological malignancies (36,37,40), while unexpectedly lower incidence on most common cancers than general population has been described (41,42). Cancer is a leading cause of mortality in PID, and thus early diagnosis and treatment of malignancy is a priority (22,43).…”

Primary Immunodeficiency

“…Interestingly, the four most common cancers routinely occurred in men and women (lung, colon, breast, and prostate cancers) do not have significant elevation in subjects diagnosed with PID [31]. Evidence also demonstrated that patients with specific forms of immunodeficiency caused by highly penetrant gene defects have higher risk of developing cancer [32].…”