Malignancy‐associated immune responses: Lessons from human inborn errors of immunity

It is widely understood that cancer is a significant cause of morbidity and mortality worldwide. Despite numerous available treatments, prognosis for many remains poor, thus, the development of novel therapies remains essential. Given the incredible success of many immunotherapies in this field, the important contribution of the immune system to the control, and elimination, of malignancy is clear. While many immunotherapies target higher‐order pathways, for example, through promoting T‐cell activation via immune checkpoint blockade, the potential to target specific immunological pathways is largely not well researched. Precisely understanding how immunity can be tailored to respond to specific challenges is an exciting idea with great potential, and may trigger the development of new therapies for cancer. Inborn Errors of Immunity (IEI) are a group of rare congenital disorders caused by gene mutations that result in immune dysregulation. This heterogeneous group, spanning widespread, multisystem immunopathology to specific immune cell defects, primarily manifest in immunodeficiency symptoms. Thus, these patients are particularly susceptible to life‐threatening infection, autoimmunity and malignancy, making IEI an especially complex group of diseases. While precise mechanisms of IEI‐induced malignancy have not yet been fully elucidated, analysis of these conditions can highlight the importance of particular genes, and downstream immune responses, in carcinogenesis and may help inform mechanisms which can be utilised in novel immunotherapies. In this review, we examine the links between IEIs and cancer, establishing potential connections between immune dysfunction and malignancy and suggesting roles for specific immunological mechanisms involved in preventing carcinogenesis, thus, guiding essential future research focused on cancer immunotherapy and providing valuable insight into the workings of the immune system in both health and disease.

malignancy and suggesting roles for specific immunological mechanisms involved in preventing carcinogenesis, thus, guiding essential future research focused on cancer immunotherapy and providing valuable insight into the workings of the immune system in both health and disease.
K E Y W O R D S immune system, inborn errors of immunity, malignancy, primary immunodeficiency BACKGROUND Inborn errors of immunity (IEIs) are genetic defects of the immune system.There are currently 485 known monogenic IEI phenotypes. 1,2 hese may manifest as increased infection susceptibility, autoimmunity/autoinflammation, or predisposition to malignancy. 1 Amongst immunodeficient patients, the second-leading cause of death is malignancy, with a higher incidence of malignancy in IEI cohorts. 3These include haematological malignancies alongside solid tumours. 4Malignancies in patients with IEIs may arise due to intrinsic causes such as inadequate immunosurveillance, or extrinsic causes such as increased susceptibility to oncogenic viruses. 3Due to the nature of IEIs, these defects shed light on critical processes involved in human immunity.][7][8][9][10][11][12][13][14][15] Key functions of immune components have been elucidated both through the study of these defects, and how they enable carcinogenesis, particularly with respect to anti-tumour immunity.We have also outlined how lessons learned from IEIs may be applied in treatment.Where possible, we have drawn conclusions from large cohort studies, but due to the rarity of these IEIs, several of these lessons come from smaller studies and case reports.

COMMON VARIABLE IMMUNODEFICIENCY
Common variable immunodeficiency (CVID) is the commonest symptomatic primary immune deficiency, covering several heterogeneous conditions which result in primary antibody deficiency. 5Diagnostic criteria of CVID may include hypogammaglobulinaemia (in the absence of an explanation), absent isohaemagglutinins and/or poor response to vaccines, and immunodeficiency onset after 2 years of age. 16Clinical manifestations of CVID may include autoimmunity, increased susceptibility to opportunistic infections, polyclonal lymphocytic infiltration and malignancy. 5One cohort study of Czech CVID patients found that the incidence of malignancy in CVID patients was over 6 times that of the general population. 17Common types of cancer seen in CVID include gastric cancer, Non-Hodgkin lymphoma and Hodgkin lymphoma. 5,17,18 Ts susceptibility to tumorigenesis may be due to inadequate immunosurveillance and protection against malignancy in CVID patients. 19Reduced T-lymphocyte proliferation has been seen in several cohort studies, [20][21][22] including a significant association between CD8 + T-lymphocyte lymphopenia and malignancy. 22alignancy in CVID patients may also be due to malignancy-associated pathogens, such as Helicobacter pylori, which is associated with gastric cancer and mucosaassociated lymphoid tissue lymphoma. 19,23,24 Hwever, this may not wholly explain the prevalence of gastric cancer in CVID patients, given that H. pylori is found in approximately 50% of the general population. 18,25 ather, chronic and frequent exposure to bacterial and viral antigens may induce chronic lymphoid stimulation and subsequent B-lymphocyte clonal expansion, leading to lymphoma. 26,27 owever, though abnormal B-lymphocyte clonal expansion has been seen in CVID, it has not been associated with malignancy. 27Variants of several DNA repair genes have been associated with CVID, including non-homologous end joining (NHEJ) genes such as DCLRE1C, PRKDC, RAG2, NHEJ1, MRE11A, ATM and NLRP2. 19The NHEJ process is key for the repair of double-stranded breaks that may otherwise lead to carcinogenesis. 19,28 dditionally, defective repair genes predispose to increased chromosomal radiosensitivity in CVID patients, which may lead to genetic instability and the subsequent development of malignancy. 19,29 owever, there are a lack of studies explicitly looking at defective DNA repair and genetic instability in CVID patients and their association with malignant manifestations, hence this interpretation is limited.A strong association between raised serum Immunoglobulin(Ig)M and lymphoid malignancy was noted in a cohort of 334 CVID patients, with a 31% increase in odds of lymphoid malignancy per additional 1 g/L of IgM. 30 Raised IgM was also associated with polyclonal lymphocyte infiltration in this study, which was a predictor of lymphoid malignancy, suggesting a twostep transformation mechanism. 30tudies in CVID patients have further elucidated the dysregulation of NF-κB1, a transcription factor which is key for B cell function. 31Mutations in NF-κB1 are inherited in an autosomal dominant pattern and may lead to hypogammaglobulinaemia and defects in Ig class switching. 32,33  possible mechanism for NF-κB1 mutations causing malignancy is that NF-κB1 mutation leads to decreased p50 expression, which then leads to hypogammaglobinaemia which in turn increases susceptibility to malignancy-associated infections such as Epstein-Barr virus (EBV). 31,32 owever, the link between NF-κB1 mutations and malignancy remains unclear: a UK cohort study highlighted a link between malignancy and mutated NF-κB1, 32 whilst a Danish and Swedish cohort study showed no significant link between mutated NF-κB1 and malignancy. 34tudies by Rezaei et al. 35 and Mahmoudi et al. 36 have shown that there are increased levels of soluble CD30 (sCD30) in CVID patients with malignancy compared to CVID patients without malignancy.Currently, it is thought sCD30 is important in maintaining the balance of type 1 (Th1) and type 2 (Th2) helper T cell responses, 36 as this facilitates the production of Th1 and Th2 cytokines and ensures they are balanced, therefore the increase in sCD30 may disturb this balance. 37Dysregulation of the Th1/Th2 response, especially increased Th2 response, has been theorised to be the cause of several malignancies. 38Mahmoudi et al. 36 state that CVID patients tend to have a more Th1-biased response, while Rezaei et al. 35 found that there were higher levels of Th2 cytokines such as interleukin(IL)-4 in their study.Other studies have found that there is an increased Th1 response in CVID patients 39 as there is increased IL-12 expression, 40 however these studies did not look into sCD30 therefore the link between increased sCD30 and its relevance to Th1/Th2 dysregulation needs to be further explored before drawing conclusions.

SEVERE COMBINED IMMUNODEFICIENCY
Severe combined immunodeficiency (SCID) is an IEI causing failure to produce T and B-lymphocytes and, depending on the mutation, can cause decreased natural killer (NK) cells. 6In general, the lack of lymphocytes and NK cells usually causes severe opportunistic infections in infants and failure to thrive. 41,42 ][45] One of the most common SCID subtypes is X-linked γ chain (γc) of interleukin (IL) receptors. 46][50] SCID has also highlighted the importance of V(D)J recombination in the immune system for the creation of antigen receptors. 51Mutations in recombinationactivating genes (RAG) 52 and Artemis protein defects 6 can cause SCID, and the mutations can also interfere with V(D)J recombination.][53] Impaired T-cell maturation leads to apoptosis of T-lymphocytes causing low circulating T-lymphocytes. 54utations in Forkhead-box N1 (FOXN1) 44 and adenosine deaminase (ADA) 47 genes can cause impaired T-cell development.Thymic aplasia can be caused by FOXN1 mutations, which in turn leads to abnormal T-cell development.Mutations in ADA cause a build-up of toxic substrates, especially in the thymus which leads to apoptosis of T-lymphocytes. 44,47,54 Wlst cohort studies in patients with SCID have been carried out, especially in patients with RAG mutations, patients with SCID tend to be successfully treated with haemopoietic stem cell transplant leading to a decreased incidence of malignancy. 55Due to the rarity of malignancy-associated SCID cases, most of the information comes from case reports and autopsy testing, so the generalised effects of SCID and the immune system cannot be drawn.Due to the almost complete absence of the immune system in SCID, 6,41,42 conclusions about the effect of SCID on specific components of the immune system, such as the effect on T-cell depletion specifically being the cause for increased infection, 43,44 may not be accurate as multiple components may be involved simultaneously in the immune phenotype observed.

X-LINKED IMMUNODEFICIENCY WITH MAGNESIUM DEFECT, EBV INFECTION AND NEOPLASM
X-linked immunodeficiency with magnesium defect, EBV infection and neoplasm (XMEN) is an X-linked disorder, resulting from a loss of function (LOF) mutation of the MAGT1 magnesium transporter. 56,57 MEN was first reported in 2011. 58As of January 2022, there have been 45 reported cases. 59Clinical features include a CD4:CD8 T-cell ratio ≤1, EBV viremia, and consequently EBVpositive lymphomas. 60XMEN may also present with autoimmunity. 61,62 mmunodeficient features include hypogammaglobulinaemia, CD4 + T-cell lymphopenia and increased viral and bacterial infection susceptibility. 60,63 GT1 is ubiquitously expressed, allowing intracellular magnesium homeostasis. 7,56 hough the importance of magnesium for T-cell function has been known for decades, 7 the role of MAGT1 has been better characterised through studying XMEN. 57MAGT1 allows the rapid influx of magnesium into T-cells following T-cell receptor (TCR) engagement.LOF mutations in MAGT1 cause defective T-cell signalling, characterised by decreased magnesium and calcium influx, and delayed and diminished phospholipase C-γ phosphorylation and activation. 7,56,63 Te MAGT1 defect also causes a chronic decrease in basal Mg 2+ concentration. 57This reduces expression of the NK group 2D (NKG2D) receptor.Physiologically, NKG2D is expressed on NK cells and cytotoxic T-lymphocytes (CTLs) and plays a key role in their cytotoxic activity by engaging NKG2D ligands expressed on malignant and EBV-infected cells.This facilitates tumour surveillance, anti-tumour and anti-EBV effects. 7,56,57,63 InXMEN, these processes are impaired.Mutations in MAGT1 have been linked to hypoglycosylation of NKG2D, leading to its insufficient expression. 64Therapeutic reinsertion of MAGT1 via CRISPR-Cas9 (clustered regularly interspaced short palindromic repeats associated with Cas9 endonuclease) has been shown to restore NKG2D expression and function in human XMEN lymphocytes. 65Additionally, it has been shown that NKG2D expression and anti-EBV effects can be partially rescued by Mg 2+ supplementation in XMEN patients, indicating the presence of a secondary magnesium transporter that substitutes for MAGT1. 57,66 wever, in a recent study of 14 CVID patients, Mg 2+ supplementation did not sufficiently improve lymphocyte function, hence the viability of this as a therapeutic option is unclear. 67earning points from XMEN have key implications for anti-tumour immunity, affecting both EBV-positive and EBV-negative malignancies.However, most XMEN literature consists of case studies, and their rarity and heterogeneity limit the strength of their conclusions.For example, while it has been believed that MAGT1 plays a key role in CTL cytotoxicity, 7,56 one case report found an XMEN patient to have intact CTL responses following TCR engagement. 63As these cases also feature novel variants, 7 it is difficult to characterise how MAGT1 mutations lead to different phenotypes.While the study of XMEN has been useful for elucidating the role of magnesium and MAGT1 in immunity, without large-scale gene studies, conclusions are limited.

WISKOTT-ALDRICH SYNDROME
Wiskott-Aldrich Syndrome (WAS) is a rare X-linked immunodeficiency syndrome caused by a LOF mutation in the WAS gene, 61 occurring in four boys per 1 million live births. 68In health, subsequently produced WAS proteins (WASp) activate polymerisation of the actin cytoskeleton, allowing growth, migration and adhesion of haematopoietic cells following activation. 62,69,70 Idividuals with Wiskott-Aldrich Syndrome display a functional deficit or absence of WASp, manifesting as immunodeficiency, thrombocytopenia and eczema.More severe phenotypes, which interestingly correspond to the extent of WASp absent, 71 result in the development of childhood malignancy at an average age of 9.5 years.These patients have a 100-fold increased risk of cancer compared to agematched healthy controls. 72By studying Wiskott-Aldrich-induced malignancies, the importance of WASp function in anti-tumour responses can be analysed.
The immunological synapse is the junction between T-cells and antigen-presenting cells (APCs), which must be intact to allow cellular adhesion and subsequent T-cell activation. 62,73 ASp-deficient patients display failure to form functional immunological synapses, resulting in impaired T-cell proliferation following TCR stimulation. 9,74 Tis subsequently impairs secretion of important antitumour cytokines including interleukin-2 and Th2 cytokines. 75The NK-cell immunological synapse is also impaired in WASp deficiency, as WASp deficiency causes decreased perforin accumulation, which has been shown to reduce the NK lytic activity to 12.1% (normal range 20.8%-40.8%) 76and this decreases the ability of the NKcell to be cytotoxic against malignant cells. 76,78 erefore, normal cancer immunosurveillance mechanisms are bypassed, possibly explaining the frequency of malignancy in this cohort.Additionally, dysfunctional CTLs induce limited immunological clearance of oncogenic viruses such as EBV, which further predisposes lymphomagenesis. 8lthough T-cell-dependent activation of the humoral response is attempted in WAS, 77 such activated B-cells mostly resemble immature cells, displaying activity levels like those observed in resting lymphocytes, suggesting impaired B-cell function.Thus, peripheral B-cells are often unresponsive to polysaccharide antigens, 69,77 thought to be mediated through reduced expression of CD23, a B-cell membrane glycoprotein, 77,78 due to a post-transcriptional defect in CD23 expression. 74Furthermore, abnormal immunoglobulin responses to EBV infection have been noted. 78,79 owever, normal humoral responses have been observed for both CMV and HSV, 80 possibly indicating an EBV-specific immunological defect in these patients.This may partially account for the incidence of malignancy, 80 although caution should be taken in drawing conclusions from this data due to small sample sizes.
Such findings provide persuasive evidence regarding the importance of functional WASp and subsequent immunological synapse formation.However, it is difficult to draw precise conclusions from this data due to the rarity of WAS.

ATAXIA-TELANGIECTASIA
Ataxia-telangiectasia is an IEI caused by recessive inheritance of mutations in the ataxia-telangiectasia mutated (ATM) gene. 81Ataxia-telangiectasia usually presents in young children as cerebellar ataxia, oculocutaneous telangiectasias and sinopulmonary infections due to immunodeficiency 81 and is associated with a higher risk of haematological malignancies. 82[85][86][87] Mutation of ATM impairs V(D)J recombination as the mutated protein is unable to stabilise the DNA breaks that occur in V(D)J recombination process, leading to decreased T and B-cell receptor repertoires. 88Furthermore, any B and T-lymphocytes that are produced may have decreased functionality as cell studies looking into T 89 and B-lymphocytes have suggested that the ATM mutation impairs T and B-lymphocyte function due to a disruption in intracellular Ca 2+ signalling after the antigen receptor is stimulated, decreased Ca 2+ signalling disrupts the differentiation and development of T and B-lymphocytes. 90 case study 10 and a cohort study 88 of ataxiatelangiectasia patients have found patients have an underdeveloped thymus and suggest this may be a cause of abnormal T-cells in the periphery and T-cell depletion in some patients.A study by Chun et al. 91 analysing the peripheral blood of four ataxia-telangiectasia patients over 20 years found that the patients had abnormal T-cell lineages with two of the patients having the abnormal presence of double-positive cells (CD4 + CD8 + ).The study suggested that the abnormal T-cell lineages could be linked to mutations in the T-cell leukaemia-1 (TCL-1) and TCL-1b genes.The presence of abnormal T-cell lineages has been linked to increased likelihood of haematological malignancies. 82,91,92 Hever, the conclusions drawn about the immune system from ataxia-telangiectasia and specifically relating certain functions to certain genes should be considered with caution.Ataxia-telangiectasia patients have chromosomal instability 90 and therefore multiple genes may be mutated, chromosomal instability also increases the risk of developing a malignancy. 93A cohort study looking into the peripheral blood mononuclear cells of ataxiatelangiectasia patients found 310 genes expressed differently compared to patients without ataxia-telangiectasia, ataxia-telangiectasia patients had increased ITGB5 which is associated with increased tumour development and decreased BACH2 expression which causes immunoglobulin deficiency, T-cell dysregulation which may lead to impaired tumour suppression. 94Chun et al. 91 attributed the presence of CD4 + CD8 + cells to TCL-1 and TCL-1b mutations rather than an ATM mutation as suggested by some mouse studies, 92 therefore effects seen in the immune system may be due to a different mutated gene than originally believed.

CH ED I AK -HIGASHI SYNDROME
Chédiak-Higashi Syndrome (CHS) is a rare autosomal recessive condition.Its common characteristics include immunodeficiency, neurological defects, oculocutaneous albinism, bleeding tendency and risk of haemophagocytic lymphohistiocytosis (HLH). 11,95 LH is a rare, lifethreatening hyperinflammatory disease usually seen in early childhood. 96Alongside the four subtypes of familial HLH defined by differing causative mutations, patients with other congenital immune deficiencies, including CHS, can develop HLH. 97The defining features of CHS are large lysosomes and lysosome-related organelles in granulocytes and other granulated cells. 11,95 tations in lysosomal trafficking regulator (LYST), a gene encoding a cytoplasmic protein that mediates lysosomal exocytosis, causes CHS. 11,95 efective LYST causes impaired lysosomal secretion, leading to defective NKcell-mediated and T-cell-mediated cytotoxicity.This is associated with the development of HLH and increased risk of malignancy.In fact, 85% of CHS patients develop HLH within the first decade of their life. 97ase studies report the development of haematological malignancies, namely lymphoma, in CHS patients. 11,98 Gven the rarity of CHS, its association with cancer has largely been anecdotal.A retrospective cohort study circumvented this by investigating relatives of children with IEIs like CHS causing defective lymphocyte cytotoxicity leading to primary HLH. 96First-degree relatives had significantly increased malignancy incidence compared to healthy controls.The authors concluded that heterozygous genetic mutations associated with HLH may carry increased malignancy risk.This observed risk of malignancy in patients with primary HLH irrespective of the cause is an important immunological principle, substantiating the role of lymphocyte cytotoxicity in anti-tumour immune responses.
The importance of the NK cell network and its ability to recognise, bind and lyse malignant cells is exemplified by CHS, which causes selective deficiency of cytotoxic NK cells. 95Chiang and colleagues 95 revealed impaired exocytosis of cytotoxic granules in NK cells and CTLs derived from CHS patients.Defective release of perforincontaining cytotoxic granules in NK cells and T-cells compromises their crucial role in controlling cancer progression through lysis of malignant cells. 96,99 e mechanism underlying cancer predisposition in CHS might be multifaceted.While inflammation importantly triggers tumour cell destruction via CTLs, NK cells and macrophages, it also increases bioactive molecules accessible to tumours, promoting tumour growth, metastasis, invasion and angiogenesis. 96This, alongside reduced immunosurveillance by CTLs and NK cells, might explain why conditions like CHS associated with HLH, a condition involving excessive inflammation, increase risk of malignancy.
There are important caveats to the literature surrounding CHS that must be considered.Our current understanding of the effect of conditions causing defective cytotoxicity on the risk of malignancy remains speculative, especially as CTLs derived from heterozygous carriers of HLH-associated mutations had no observable functional impairment. 96Furthermore, investigation into the role of lymphocyte cytotoxicity in immune responses to malignancy has been hindered by the high mortality rate in conditions like CHS due to complications like HLH. 96

HYPER IgE SYNDROME
Hyper Immunoglobulin (Ig) E syndrome (HIES) is an uncommon condition characterised by a raised serum IgE (≥2000 IU/mL) alongside eczema, recurrent skin and pulmonary infections, and skeletal/connective tissue defects. 12,100 IES is classified as autosomal dominant (AD-HIES) 12,101 or autosomal recessive (AR-HIES).102 Causal mutations in signal transducer and activator of transcription 3 (STAT3) have been found in AD-HIES.100,101,103 Gain of function mutations in STAT3 have been linked to various cancers, such as diffuse B-cell lymphoma, 104 and typically correlate with poor prognosis, [104][105][106] and typically correlate with poor prognosis. 105,106Increased STAT3 function leads to the buildup of immunosuppressive Treg cells 107,108 which are well-known for their multifaceted role in promoting cancer through tumour immune escape and angiogenesis. 109urthermore, elevated STAT3 functioning has been shown to restrict cytolytic functions of CD8 + T-cells, NK cells and neutrophils, and inhibit dendritic cell maturation 106 and antigen presentation.107 These findings substantiate the importance of these cells in anti-tumour immunity.
AR-HIES also confers a high risk of malignancy. 102It is commonly caused by LOF mutations in the dedicator of cytokinesis 8 (DOCK8). 110In addition to lymphomas, patients with DOCK8 deficiency are susceptible to epithelial cancers. 111In a multicentre study, 4 the highest rate of malignancy was recorded amongst DOCK8-deficient patients.The primary driver of malignancy in DOCK8-deficiency appears to be uncontrolled viral infection due to insufficient immune responses. 4This is illustrated by a case of human papilloma virus-induced squamous cell carcinoma in an AR-HIES patient with homozygous DOCK8 mutations. 102Susceptibility to infections, including herpetic viral skin infections, likely result from the defective DOCK8-regulated actin skeleton.Insufficient coordination of the actin cytoskeletal network leads to T and NK cell death when migrating through compact tissues such as collagen-rich skin, limiting the frequency of skin-resident memory CD8 + T-cells thus increasing susceptibility to skin infections. 107OCK-8-mediated regulation of the actin cytoskeleton is also responsible for the accumulation of adhesion molecules and cytolytic granules at immune synapses. 106In DOCK8-deficient patients, the resultant impaired interactions within immunological and cytotoxic synapses impair B, T and NKT-cell survival and disrupt NKmediated cytotoxicity. 106Alongside viral infection, the lack of cytolytic granules at immune synapses may contribute to carcinogenesis.This demonstrates the importance of CTL and NK cells in controlling viral infections and killing cancer cells via immune synapses. 112,113 t should be noted there are some reports of DOCK8-deficient patients without hyper-IgE 114 and there is an observed association between DOCK8 deficiency and a novel variant of combined immunodeficiency, 115 suggesting DOCK8 deficiency should be reclassified as a distinct entity to HIES with a poorer prognosis.
A caveat to consider is that the literature mainly consists of case studies due to the rarity of HIES.This hinders the ability of future work to delineate the mechanisms by which DOCK8-deficiency affects immune system parameters to refine our understanding of the associated cancer predisposition.Moreover, the role of STAT3 in cancer progression must be clarified as our understanding is muddied by findings that hyperactive STAT3 correlates with better prognosis in certain cancers, such as soft tissue leiomyosarcoma. 116

HYPER IgM SYNDROME
Hyper IgM Syndrome (HIGM) is characterised by high levels of IgM and low levels of IgG, IgA and IgE, leading to recurrent infections and a predisposition to malignancies. 13,117 his immunoglobulin imbalance is theoretically due to impaired immunoglobulin class switching by B-cells. 13Associated genes include activation-induced cytidine deaminase (AICDA), uracil-DNA glycosylase (UNG) and phosphoinositide 3-kinase catalytic delta component (PI3KCD).HIGM can be inherited in an autosomal recessive (AICDA and UNG) or autosomal dominant (PI3KCD) pattern. 118The most common form of HIGM is X-linked HIGM (XHIGM), typically caused by a mutation in the CD40 ligand gene (CD40LG), which codes for CD154, found on the T-cell surface.CD154 allows T-cell driven immunoglobulin class switching. 118IGM has shed light on several adaptive immunity processes.One study of XHIGM patients with CD40LG mutations found that, upon stimulation with activated T-cells, their APCs did not produce IL-12, reducing TNFα induction and IFN-γ production by T-cells. 119D154 was directly implicated in regulating the T cell response, as IFN-γ production was restored in the presence of CD154 trimer.119 These patients also had reduced mature (CD45RO + ) T-cells.119 These findings indicate that CD154 plays a key role in the differentiation of T-cells into the Th1 phenotype (through IL-12 secretion), and the priming and post-thymic maturation of T-cells.119 Another study of XHIGM patients found that they had impaired antigen-specific T-cell proliferation in response to Candida, and the diphtheria and tetanus toxoids, indicating that CD154 facilitates antigen-specific cellular responses.117 The impaired CD40-CD154 interaction has previously been posited as mechanism for XHIGM-associated malignancy, as this interaction typically induces apoptosis in infected cells.120 However, this speculation was limited to infection-associated malignancies. 120While HIGM has elucidated several components of adaptive immunity, the heterogeneity of causative mutations may lead to conflicting evidence. Forexample, a study of patients with PIK3CD HIGM found that their B-cells were able to produce class-switched immunoglobulins, indicating that hyper-IgM was not due to an intrinsic defect in B-cell class switching, 121 despite this generally being cited as the underlying mechanism of HIGM in the literature reviewed here.Going forward, different forms of HIGM should be clearly distinguished from one another, as conclusions from one form may not be broadly applicable, particularly if they differ in pathophysiology.

SPECIFIC IgA DEFICIENCY
IgA Deficiency is a common primary immunodeficiency observed in 1/600 individuals in the Western world. 122he condition is characterised by undetectable or reduced levels of blood and secretory IgA (sIgA), the main function of which is to protect mucosal surfaces from infection. 14gG and IgM serum levels can remain normal, which is known as Specific IgA Deficiency (SIgAD). 15SIgAD can present with increased susceptibility to mild respiratory or gastrointestinal infections which are often refractory to antibiotic treatment.However, more often, patients are completely asymptomatic, and therefore worldwide prevalence is likely underestimated. 123hile the clinical ramifications are minor in the short term, there is some evidence to suggest that SIgAD may increase the risk of some cancers. 122Early investigations revealed statistically significant increases in the frequency of SIgAD cases in cancer patients compared to healthy populations.However, it was noted that the incidence of SIgAD did not significantly differ from that in other patient groups.It is unclear whether this was due to patients with SIgAD being referred to the hospitals in question or the lack of SIgAD being an unrealised underlying abnormality in general medicine patients. 124Most recently however, Ludviggson and colleagues found that a diagnosis of SIgAD increased the risk of any cancer by 31%, and gastrointestinal cancer specifically by 64%, even when adjusting for conditions strongly related to SIgAD such as Coeliac Disease. 122sIgA has been shown to be important in regulating the intestinal microbiome, 15,125 and ensuring that mucosal surfaces are protected from pathogens, 14,15,125 so the increased incidence of gastrointestinal cancers in patients with SIgAD may be due to intestinal microbiome dysregulation due to decreased sIgA. 122Additionally, SIgAD may also progress to CVID, suggesting that they are both part of the same spectrum of immune disorders, 126 which may indirectly relate to IgA deficiency and CVID-associated malignancies.

TREATMENT
The treatment of IEI-induced malignancy is complicated by the fact that conventional chemotherapy regimens worsen current immunodeficient states, making patients extremely vulnerable to life-threatening infections. 72educing immune dysregulation will not only prime immune responses against tumour cells but will also allow for a more effective chemotherapeutic regime.Initially, haematopoietic stem cell transplant (HSCT) was the mainstay for curative treatment of IEIs. 69,127 owever, the requirement of human leukocyte antigen-matched donors to reduce the risk of graft-versus-host disease presents a huge challenge due to unavailability. 79Furthermore, the efficacy of adoptive therapies including chimeric antigen receptor T-cell (CAR-T) may be limited in this population given the potential increased risk of carcinogenesis when complex immunomodulatory mechanisms are used in a background of significant immune dysfunction. 128n recent years, gene therapy has emerged as an alternative to HSCT in patients with IEIs caused by LOF mutations.This involves the use of a viral vector, particularly retroviruses and lentiviruses, which irreversibly incorporate the wild-type gene into haematopoietic stem cells. 129nitial studies reported successful treatment of ADA-SCID with gene therapy, 130 and since then promising results have been shown in chronic granulomatous disease, X-linked-SCID and Wiskott-Aldrich Syndrome. 130,131 ch studies have observed normalisation of T-cell, B-cell and NK cell function. 132However, some studies have reported safety concerns due to subsequent development of leukaemias or myelodysplasias in patients with IEIs.These adverse events have been mitigated recently by using lentiviruses with self-inactivating configurations. 133,134 Hwever, precisely imitating physiological gene expression using viral vectors still remains difficult and longterm safety has limited the approval of vector-based gene therapy. 135Gene editing techniques, such as CRISPR-Cas9 can be a more accurate method of altering genetic material at a base-pair level. 136Gene editing can precisely target and modify, by adding or removing DNA sequences, specific genetic mutations known to cause IEIs.4][135] However, precisely imitating physiological gene expression using viral vectors still remains difficult and long-term safety has limited the approval of vector-based gene therapy. 135tudies have shown that individuals with IEIs are still able to produce long-lasting neutralising antibody responses to some vaccines, 137 therefore prophylactic EBV vaccines present as a potential treatment option to reduce the high frequency of EBV-associated malignancy in this cohort.Numerous clinical trials have reported successful responses to prophylactic EBV vaccines, 138 and recently, one group has commenced Phase 1 clinical trials for a novel mRNA EBV vaccine. 139mRNA vaccines are of particular interest due to their promising safety profile and versatility, 140 thus, results of this trial are eagerly anticipated, especially in relation to individuals with IEIs.Alternatively, antibody responses to vaccination can be boosted using immunoglobulin replacement therapy (IVIg). 141Studies have shown that individuals with IEIs are still able to produce long-lasting neutralising antibody responses to some vaccines, 137 therefore prophylactic EBV vaccines present as a potential treatment option to reduce the high frequency of EBVassociated malignancy in this cohort.Numerous clinical trials have reported successful responses to prophylactic EBV vaccines, 138 and recently, one group has commenced Phase 1 clinical trials for a novel mRNA EBV vaccine, 139 mRNA vaccines are of particular interest due to their promising safety profile and versatility, 140 thus, results of this trial are eagerly anticipated, especially in relation to individuals with IEIs.Alternatively, antibody responses to vaccination can be boosted using IVIg. 141In fact, additional studies have shown that IVIg alone is effective at reducing malignant co-morbidities in patients with CVID by improving NK lytic function, which can also be enhanced using tumour-directed monoclonal antibodies which induce the release of perforin and granzymes, enhancing anti-tumoural immune effects. 142,143

CONCLUSION
In conclusion, IEIs can affect a huge range of immunological mechanisms involved in carcinogenesis.Reviewing seminal and recent literature regarding IEI-associated malignancy highlights important correlations between particular genes, subsequent immune cell effects, and cancer immunology.This review provides insight into such immunological mechanisms and reports meaningful associations between specific immune defects and cancer.In particular, the damaging downstream consequences of dysfunctional anti-EBV responses and impaired immunosurveillance.In the future, larger cohort studies will further elucidate important mechanisms of carcinogenesis and anti-tumour immunity which can inform the development of novel cancer immunotherapies for years to come.