Updates of cancer hallmarks in patients with inborn errors of immunity

INTRODUCTION

Inborn errors of immunity (IEI, previously labeled as primary immunodeficiency) are a group of diseases constituted approximately 500 known monogenic defects. One-third of identified genes have a direct role in tumorigenesis and the development of different types of cancer hallmarks.

Hallmarks of cancer were proposed with the rationale of better understanding human cancer etiological multistep processes. These hallmarks have also been further developed based on the cornerstone mechanisms discovered in different human malignancies. Currently, the last update of these hallmarks of cancer contains 14 major entities. There were 10 hallmarks proposed until 2011, which are 8 hallmark capabilities: sustaining proliferative signaling, evading growth suppressors, activating invasion and metastasis, enabling replicative immortality, inducing angiogenesis, resisting cell death [1], and 2 enabling characteristics: reprogramming cellular metabolism and avoiding immune destruction. Lately, additional two emerging hallmarks ‘Unlocking phenotypic plasticity’ and ‘Senescent cells’ and two enabling characteristics ‘Nonmutational epigenetic reprogramming’ and ‘Polymorphic microbiomes’ have been proposed (Fig. 1) [2▪▪].

F1FIGURE 1:

Updates on recently discovered monogenic defects and newly described cancer hallmarks in different types of monogenic inborn errors of immunity according to the International Union of Immunological Societies classification. IUIS – Table1: immunodeficiencies affecting cellular and humoral immunity; IUIS – Table 2: combined immunodeficiencies with associated or syndromic features; IUIS –Table 3: predominant antibody deficiencies; IUIS –Table 4: diseases of immune dysregulation; IUIS – Table 6: defects in intrinsic and innate immunity; IUIS – Table 7: autoinflammatory disorders; IUIS –Table 9: bone marrow failure. IUIS, International Union of Immunological Societies.

Previously, we mapped functional capabilities among 450 IEI germline mutations in 10 cancer-hallmarks to the distinguishable steps of malignancy pathogenesis [3▪▪]. In this review, the integrative concept of new dimensions of four oncologic hallmarks associated with IEI is presented. Moreover, 55 novel genes with enigmatic pathogenic roles in different immune cell subsets have been discovered recently and updated in the International Union of immunological (IUIS) classification [4▪▪]. Therefore, we introduce and link these new genes with all the previous and new hallmarks of cancer in the following section. 

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UNLOCKING PHENOTYPIC PLASTICITY

One of the main emerging hallmarks of cancer is unlocking phenotypic plasticity. Cellular differentiation is considered as a clear blockade for neoplasia. The majority of neoplastic cells escape the terminal differentiation through three main mechanisms including blocked differentiation, de-differentiation or trans-differentiation.

Blocked differentiation

Of note, many known IEI genes have a significant role in both adaptive and innate immune cell differentiation. Well described genes have been reported to be associated with terminal lymphocyte differentiation, including regulators of phosphoinositide 3-kinases (PI3Ks) pathway (PIK3CD and PIK3R1 required for CD4+ T-cell differentiation through AKT and mTOR pathway [5] and B-cell differentiation via FOXO activation [6–8]), the regulator of nuclear factor kappa B (NF-κB) pathway (NFKB1 and NFKB2 are required for plasmablast cell differentiation through the NF-κB signaling pathway [9,10]), MCM4 and MCM10 (required for natural killer (NK) cell differentiation) [11–13]. Moreover, X-linked IPEX syndrome (FOXP3 deficiency) and CD25 deficiency (IL2RA) affect T-cell differentiation into regulatory T cells and then result in lymphoproliferation and, subsequently, lymphoma [14,15]. Therefore, monogenic mutations in the genes, which can block the differentiation but not proliferation might be a tumor-predisposing factor because cancer cells enable to escape cell terminal development and resume proliferative expansion [16].

De-differentiation and trans-differentiation

Microphthalmia-associated transcription factor (MITF) acts as a master of melanocyte differentiation [17], and it has been clearly shown that low MITF levels are related to malignancy [18]. Malignancies in patients with PTEN deficiency might also be associated with MITF degradation and destabilization through deregulating humoral immune response via increasing the PI3K/AKT activity [19–21]. Transdifferentiation (or metaplasia) can also be identified in many IEI monogenic defects as a predisposing stage to the development of neoplasia, mainly in nonhematologic cancers [22]. IEI patients with chronic tissue damage and the subsequent unregulated inflammatory response can often lead to the formation of fibrotic tissue that prevents effective regeneration mainly in the lung (e.g. interstitial lung disease in common variable immunodeficiency) and liver (Tricho-Hepato-Enteric syndrome in TTC37 and SKIV2L deficiencies). The proposed pathology for this phenomenon linked the oxidative stress and cytokines released from innate immune cells inducing transdifferentiation of fibrogenic myofibroblasts, thereby contributing to fibrosis in the periportal parenchyma [23]. Other changes in unlocking phenotypic plasticity and differentiation can also induce IEI patients to develop malignancy via modification of epigenetic alteration of hematopoietic stem cells, which are separated in a distinct cancer hallmark.

NONMUTATIONAL EPIGENETIC REPROGRAMMING

The aberration of epigenetic regulation (DNA methylation, chromatin remodeling and histone modifications) on tumorigenesis is crucial and now is well described with hallmark abilities [24,25]. Fine-tuning of epigenetic processes in the immune system is required for punctual gene transcription during differentiation of the hematopoietic stem cell (HSC) and lymphoid and myeloid lineage commitment. Genetic defects in some IEI genes potentially can affect the DNA methylation signatures and histone modification patterns and contribute to the pathogenesis of clinical manifestations, including malignancy phenotype [26]. Moreover, this mechanism has been proposed as the main cause of some unknown IEI disorders without monogenic mutation but with high susceptibility to cancers including common variable immunodeficiency or IgA deficiency [27–29]. For instance, alteration in DNA methylation associated with some transcription factors (namely PAX5, E2F and EBF1) have been shown to lead to the blockade of the early stages of B-cell development (from pro-B to pre-B cells) in selected patients with common variable immunodeficiency [30,31]. Moreover, studies on the DNA methylome of these patients highlighted the gross demethylation during the late stage of B-cell development mainly in the memory B-cell stage [32].

Some other IEI genetic defects are because of well known mutations in epigenetic factors including DNA methyltransferase 3 beta (DNMT3B) and its associated molecules ZBTB24, CDCA7 and HELLS [33]. These defects are classified as immunodeficiency with centromeric instability and facial anomalies (ICF) syndrome. Genomic instability of pericentromeric and telomeric regions, and more generalized whole-genome hypomethylation have been observed. Although they are extremely rare syndromes with few patients followed until adulthood, cancers and mainly lymphoma because of abnormal early maturation of lymphocytes have been reported in some ICF patients [34]. The other two main IEI genes, which are controlling lymphocyte development and lineage commitment are activation-induced cytidine deaminase (AID) and Tet methylcytosine dioxygenase 2 (TET2). AID is not only responsible for converting cytosines in DNA to uracil during class-switch recombination and somatic hypermutation, but is also implicated in the demethylation of 5-methylcytosines (5mC) to thymine, particularly during early embryogenesis [35]. Similarly, TET2 in HSCs can oxidize 5mC to 5-hydroxymethylcytosine (5hmC) essential for the development of B and T cells [36]. Defects in both genes also have been reported to predispose IEI patients to hematological neoplasia [3▪▪].

Another level of epigenetic control at the DNA level, which has been connected to IEI genetic defects occurs at telomeric sequences. It is well known that the double-stranded repeat structure of telomeres protects genome stability together with heterochromatin domains of subtelomeric regions during rapid-cell replications as one of the main characteristics of highly proliferative immune cells. Recombination between telomeric sequences or activity of telomerase as reverse transcriptase protects telomeric repeats [37]. Some IEI monogenic defects can lead to telomere decreasing to a critically short length and result in epigenetic defects at subtelomeres mainly at histone and DNA modifications. These patients (with mutations in DKC1, TERC, TERT, NOP10, NHP2 and TINF2 genes) are known as dyskeratosis congenita or Hoyeraal Hreidarson syndrome with the main feature of bone marrow failure and hematopoietic malignancies. All these proteins function within the ribonucleoprotein complex of telomerase including the catalytic subunit (TERT), its RNA component (TERC), and the four major associated dyskerin proteins [38].

More recently, proteins that control the process of histone modifications have been identified as the main cause of syndromic IEI known as Kabuki syndrome. The main two proteins associated with this syndrome are histone KMT2D methyltransferase (on H3K4 position) and histone demethylase KDM6A (on H3K27 position) whose expression regulates embryogenesis, particularly the development of lymphocytes [39,40]. On the other hand, the predominant gene deletion associated with IEI in DiGeorge syndrome (22q11.2 microdeletion) is TBX1 (T-box 1), which is also a methyltransferase (on H3K4 position similar to KMT2D), and can lead to multiorgan defects and immunodeficiency mainly because of absence of thymus and thymic development of T cells [41]. Both patients with Kabuki syndrome and Digeorge syndrome were reported to suffer from malignancies mainly lymphoma [3▪▪].

Moreover, several transcription factors (TFs) that control the harmonic expression profile after specific immune activation or synapses perform epigenetic regulation on the promotors of targeted genes via their motif. Mutation in these transcription factors can be detected in certain types of IEIs [4▪▪]. These monogenetic defects will influence the epigenetic process, such as chromatin accessibility [42–44] and posttranscriptional modification [45,46]. One of the main TFs is IKAROS, encoded by the IKZF1 gene, which is considered a critical factor for early B-cell development through the energy–stress sensor AMPK pathway [47]. Mutations of IKZF1 are associated with defective development of T cells, B cells and NK cells [48,49]. IKZF1 monogenic mutations are considered the main predisposing reason for B-cell acute lymphoblastic leukemia (B-ALL) transformation in these patients [50] and are classified as ‘sustaining proliferative signaling’ hallmarks [3▪▪]. As one of the proteins in the IKZF family, AIOLOS, which is encoded by IKZF3, the AIOLOS-G159R variant can cause defective IKAROS binding site activity by forming IKAROS-AIOLOS-G159R heterodimers, which are considered to cause heterodimeric transcription interference [51]. With higher susceptibility to Epstein–Barr virus (EBV) infection, patients with AIOLOS-G159R autosomal dominant variant developed B-cell lymphoma.

SENESCENT CELLS

Cellular senescence leads to ‘senescence-associated secretory phenotype (SASP)’, including over-production of chemokines, cytokines, chronic inflammation and processes alteration of nonsenescent neighboring cells, which has been verified to promote tumor development and malignant progression [52–55]. SASP is typically associated with the DNA damage response (DDR). Persistent DDR can promote SASP by increasing cytosolic chromatin fragments (CCFs) [56]. Thus, monogenic diseases of DNA repair may affect the induction of senescence markers [57]. For example, ATM mutation is associated with mitochondrial dysfunction-induced SASP by triggering the STING-dependent pathway [58]. NBS1 mutation modulates SASP in stress-induced signaling activation of the P38/MK2 pathway [59]. Similarly, HSCs from IEI patients with telomeric dysfunction as mentioned above with dyskeratosis congenita or Hoyeraal Hreidarson syndromes can show high DNA damage levels and become senescent [60].

Apart from the DNA repair syndrome, SASP is a very common phenomenon in the disease of immune dysregulation due to uncontrolled chronic inflammatory reactions. These continued activations and inflammation lead to reduced expression of co-stimulatory CD28 or CD27 molecule on CD45RA+ CD4+ T cells and present a reduced antigen-dependent proliferation but increased inflammatory cytokine production. On the other hand, CD8+ T cells switch from the typical T-cell receptor (TCR)-mediated activity to an NK-like activity by expressing protein complexes typical of NK cells [61,62]. A typical known mutation associated with premature immunosenescence and accelerated inflammation is Tripeptidyl peptidase II (TPP2) deficiency. The homeostatic function of TPP2 is downstream of proteasomes in cytosolic proteolysis and contributes to antiapoptotic phenotype, particularly in CD8+ T cells. Although the majority of TPP2 cases are pediatric patients, lymphoproliferative diseases are one of the main manifestations of the disease [63,64].

POLYMORPHIC MICROBIOMES

Microbiomes, including commensal bacteria and fungi, are recently expansively identified for their diverse impacts on the mucosal area of the gastrointestinal tract and respiratory system, and are considered to have an association with cancer phenotypes [2▪▪]. Over 50% of IEI patients present with gastrointestinal diseases, among which, CVID is associated with higher susceptibility to diverse complications, including chronic diarrhea, nodular lymphoid hyperplasia, liver and biliary tract diseases [65] and 10-fold increase in risk of gastrointestinal cancer compared with immunocompetent individuals [66]. NFkB1 expression is necessary for epithelial cells to regulate the bacterial barrier [67]. Virulence factors produced by Helicobacter pylori have been proposed as one of the driving reasons leading to gastric cancer through aberrant Janus kinase (JAK)-signal transducer and activator of transcription (STAT) signaling and inflammatory mediators by loss of NF-κB1[68]. Therefore, monogenic diseases will influence the susceptibility to develop malignancy, such as NFKB1 and NFKB2 deficiencies [66,69–71]. Microbiomes maintain homeostasis and avoid microbial translocation in the gastrointestinal system through the production of antimicrobial peptides (AMP) by a downstream MyD88-dependent pathway [72,73]. Of note, IEI genetic defects related to the MyD88 pathway (such as TLR3, TLR7, TLR8, IRAK4 and IKBA) may increase microbial translocation by dysregulating the immune system [74,75].

Microbiome-related metabolites influence the innate immunity of homeostatic interaction in the gastrointestinal system [76–79]. IEI monogenetic diseases have effects on the cellular pathways among innate cells in the gastrointestinal system, including monocytes, macrophages, innate lymphoid cells, γδT cells, and mucosal-associated invariant T (MAIT) cells and NK cells. Interferon-gamma (IFN-γ) is critical for gastrointestinal innate immunity against intracellular bacterial infections and drives immunostimulatory impact. In the microbiome of mucosal area, macrophages are stimulated and produce IL-1 and IL-23. γδT cells are activated by the IL-2 and IL-23, then produce IL-17 for further adaptive immunity [80]. MAIT cells particularly respond to a wide range of microorganisms and produce IL-17 and IFN-γ to perform immune stimulation [81]. Of note, IFN-γ receptor 1 (IFNGR1) deficiency and IFN-γ receptor 2 (IFNGR2) deficiency are linked to EBV-associated lymphoma and intestinal pseudotuberculosis by impairing the downstream immune cells binding and stimulating by IFN-γ [65].

Adaptive immunity against the mucosal microbiome can be affected by the mutations associated with Th17 cells, FOXP3+ regulatory T cells, B cells, CD4+ T cells, CD8+ T cells, and follicular helper T (Tfh) cells. Therefore, the monogenic diseases that affect V(D)J recombination and class-switch recombination and reduce the diversity of the secretory IgA repertoire (eg. RAG1, RAG2, ATM, BLM and MSH6 deficiencies) and thus predispose towards microbiota dysbiosis and gastrointestinal tumorigenesis [65,79,82] Moreover, the function of controlling intestinal inflammation by IL-10 (IL10, IL10RA and IL10RB deficiencies) is of importance for promoting gut homeostasis [83–85]. Moreover, hypomorphic defects of cellular immunity by dysfunction of T cells can present long-term chronic diarrhea and gastrointestinal cancer development consequently due to dysbiosis.

NOVEL INBORN ERRORS OF IMMUNITY GENES ASSOCIATED WITH HALLMARKS OF CANCER

We reported that more than one-third of IEI monogenic defects have been linked with cancer hallmarks according to the IUIS classification of 2020 [3▪▪,86]. Among 55 novel IEI genes discovered during the last 2 years [4▪▪], although the number of patients is still very limited for each disease to guarantee the association or dissociation from malignancy, we have reported here 15 genes in which cancer is a component of the main clinical phenotype observed among these rare case reports and tried to classify them mechanistically based on the known cancer hallmarks (Table 1).

Table 1 - Demographic and clinical presentation of patients with novel inborn errors of immunity monogenic defects and predisposition to lymphoproliferation and malignancies IUIS Gene Protein Pathway Patient ID index of paper Gender Mutation Malignancies Predisposition to lymphoproliferation Hallmarks PMID Year Table 1 IKZF1 IKAROS: zinc finger transcription factor AMPK pathway PALL 1-3 UN Haploinsufficiency (HI) mutations B-ALLSolid pseudopapillary pancreatic tumor Autoimmune disease; immune dysregulations; recurrent/severe bacterial infections Sustaining proliferative signaling PMID: 33392855 2021 SASH3 SLY: SH3-containing lymphocyte protein TCR-signaling pathway P1 M R347C LGL proliferation Recurrent pulmonaryinfections, skin/soft tissueinfections, warts Avoiding immune destruction PMID: 33876203 2021 IKZF2 HELIOS: zinc finger transcription factor IFN-γ and IL-2-signaling pathways P2 M Y200X HL Chronic lymphadenopathy Tumor-promoting inflammation PMID: 34826260 2021 P.C1 M V347M HLH Chronic active EBV PMID: 34920454 2022 P.D1 F R106W HLH Recurrent maxillary sinusitis Table 2 MCM10 MCM10: minichromosomal maintenance complex member 10 DNA repair pathway P1 M R426C and R582X HLH Lymphadenopathy, CMV infection, NK Deficiency Genome instability and mutation PMID: 32865517 2020 DIAPH1 DIAPH1/mDIA1: evolutionarily conserved formin diaphanous homolog 1 Rho-mDia1 pathway P1 M c. 684+1G>A DLBCL Bacterial otitis media, candida,mycobacteria, VZV, HSV, EBV, Molluscum contagiosum Avoiding immune destruction PMID: 33662367 2021 P2 M c. 684+1G>A HL-like Respiratory infections P6 F F923fsX DLBCL Candida, EBV, CMV infection IKZF3 AIOLOS: zinc finger transcription factor B-cell development P1 F G159R B-cell lymphoma EBV infection, recurrent sinopulmonary infections Nonmutational epigenetic reprogramming, avoiding immune destruction, activating invasion and metastasis PMID: 34155405 2021 P2 M G159R B-cell lymphoma EBV infection, recurrent sinopulmonary infections PA.II.1 F N160S CLL; metastatic melanoma Recurrent sinopulmonary infections; Severe hypogammaglobulinemia PMID: 34694366 2021 CD28 CD28: T-cell receptor TCR-signaling pathway P1 F G18R Benign epithelial tumor Severe HPV infection, CMV, EBV high, parainfluenza positive Avoiding immune destruction PMID: 34214472 2021 P2 F G18R - Severe HPV infection; CMV, EBV high, heavy warts P3 M G18R - Severe HPV infection; EBV high, heavy warts Table 3 PIK3CG PI3Kγ: phosphatidylinositol 3-kinase-gamma PI3K–AKT–mTOR pathway P1 F R982fsX and R2021P - Antibody defects;Lymphadenopathy/splenomegaly Tumor-promoting inflammation PMID: 31554793 2019 P1 F R49S and N1085S HLH-like Systemic inflammation PMID: 33054089 2020 CTNNBL1 CTNNBL1: β-catenin–like protein 1 protein AID-associated pathway P1 F M466V - Progressive hypogammaglobulinemia; autoimmune cytopenias; recurrent infections Genome instability and mutation PMID: 32484799 2020 Table 4 RHOG Rho G: Ras homolog gene G Cytotoxic lymphocytes transduction pathway P1 M E171K HLH Avoiding immune destruction PMID: 33513601 2021 SOCS1 SOCS1: suppressor of cytokine signaling 1 Type I and type-II IFN-signaling pathway P1 M A37RfsX48 - Anemic and neutropenic; multisystem inflammatory syndrome; Evans syndrome; immune thrombocytopenia Tumor-promoting inflammation PMID: 32853638 2020 P4 M A9Pfs∗76 HL Coeliac disease psoriasis TET2 TET2: ten-eleven translocation methylcytosine dioxygenase 2 Hematopoiesis cell differentiation and development P1 M H1382R Lymphoma Recurrent respiratory tract infections; bronchiectasis; Herpes viral infection; lymphadenopathy; hepatosplenomegalyAutoimmune cytopenias; autoantibodies Nonmutational epigenetic reprogramming PMID: 32518946 2020 P2 M H1382R Lymphoma Recurrent respiratory tract infections; bronchiectasis; herpes viral infection; lymphadenopathy; hepatosplenomegalyAutoimmune cytopenias; autoantibodies P3 F Q1632X Lymphoma Recurrent respiratory tract infections; bronchiectasis; herpes viral infection; lymphadenopathy; hepatosplenomegaly Table 6 NOS2 NOS2: nitric oxide synthase 2 TLR-dependent pathway P1 F I391IfsX26 - EBV infection;Fatal CMV infection Activating invasion and metastasis PMID: 31995689 2020 ZNFX1 ZNFX1: zinc finger nfx1-type domain containing protein 1 dsRNA virus sensor P1-P15 UN K133XT166YfsX17R334QR377QH542CfsX41R900MfsX5I1154TC1264SC1292SE1727KX11 HLH; HLH-like Severe RNA viral infection; inflammatory diseases; multisystem inflammation Activating invasion and metastasis PMID: 33872655 2021 TLR8, GOF TLR8: toll-like receptor 8 TLR pathway P1 M P432L - Lymphadenopathy, infection: Clostridium septicum bacteremia Tumor-promoting inflammation PMID: 33512449 2021 P2 M P432L - Lymphadenopathy, infection: Pneumonia and otitis media P3 M F494L – Lymphadenopathy, infection: lymphadenitis P4 M P432L – Lymphadenopathy, infection: Nocardia P5 M P432L – Lymphadenopathy, idiopathic thrombocytopenia; lymphadenopathy, recurrent GI inflammation/infection P6 M G527D – Lymphadenopathy, infection: otitis media, fungal infections Table7 SYK, GOF SYK: spleen tyrosine kinase ITAM-based signaling pathway P1 F S550Y – Lymphadenopathy, hypogammaglobulinemia; recurrent infections; intestinal inflammation Avoiding immune destruction PMID: 33782605 2021 P2 F S550F – Hypogammaglobulinemia; recurrent infections; intestinal inflammation P3 M S550F

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