Increased Risk for Malignancies in 131 Affected CTLA4 Mutation Carriers

Abstract

Background: Cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) is a negative immune regulator on the surface of T cells. In humans, heterozygous germline mutations in CTLA4 can cause an immune dysregulation syndrome. The phenotype comprises a broad spectrum of autoinflammatory, autoimmune, and immunodeficient features. An increased frequency of malignancies in primary immunodeficiencies is known, but their incidence in CTLA-4 insufficiency is unknown.Methods: Clinical manifestations and details of the clinical history were assessed in a worldwide cohort of 184 CTLA4 mutation carriers. Whenever a malignancy was reported, a malignancy-specific questionnaire was filled.Results: Among the 184 CTLA4 mutation carriers, 131 were considered affected, indicating a penetrance of 71.2%. We documented 17 malignancies, which amounts to a cancer prevalence of 12.9% in affected CTLA4 mutation carriers. There were ten lymphomas, five gastric cancers, one multiple myeloma, and one metastatic melanoma. Seven lymphomas and three gastric cancers were EBV-associated.Conclusion: Our findings demonstrate an elevated cancer risk for patients with CTLA-4 insufficiency. As more than half of the cancers were EBV-associated, the failure to control oncogenic viruses seems to be part of the CTLA-4-insufficient phenotype. Hence, lymphoproliferation and EBV viral load in blood should be carefully monitored, especially when immunosuppressing affected CTLA4 mutation carriers.

What did we learn from CTLA‐4 insufficiency on the human immune system?

“…One case report suggested that a rare heterozygous variant in Janus kinase‐3 ( JAK3 ) in addition to the CTLA4 mutation is associated with the disease onset of CTLA‐4 insufficiency; however, screening of 52 additional CTLA4 mutation carriers did not reveal another individual carrying a missense mutation in JAK3 . A significant association between male gender and the occurrence of clinical symptoms was seen in 133 CTLA‐4‐insufficient individuals, however, in an even larger cohort of currently 182 CTLA‐4‐insufficient individuals, this association is no longer seen (C. Schwab, A. Gabrysch, & D. Egg, unpublished data). A significant decrease in the total CTLA‐4 expression in affected mutation carriers in comparison to unaffected mutation carriers was seen in a total of 19 analyzed mutation carriers .…”

“…In addition, CTLA‐4‐insufficient patients had infections dominated by bacterial infections in the respiratory tract, and Epstein‐Barr virus (EBV) and cytomegalovirus (CMV) reactivations, including EBV‐induced hemophagocyticlymphohistiocytosis (HLH) and CMV‐associated diarrhea or gastritis . Approximately 12% of the affected CTLA4 mutation carriers had malignancies: the most frequent malignancy observed in CTLA4 mutation carriers was lymphoma, including EBV‐associated diffuse large B cell lymphoma, Burkitt lymphoma, and Hodgkin lymphoma . Egg et al showed that seven of ten CTLA‐4‐insufficient patients with lymphoma and three of five patients with gastric cancers were EBV‐associated.…”

“…Although CTLA‐4 is highly expressed on CD8 + T cells, Schwab et al showed that the number of CD3 + CD8 + cytotoxic T cells was normal in most of the affected carriers, while the proliferation and activation of CD8 + T cells was reported to be enhanced by blocking CTLA‐4 . Taking the development of viral infections and malignancy in CTLA‐4‐deficient individuals into account, as described above, the role of CTLA‐4 on CD8 + T cells might be important to keep the immunological balance between activation and suppression …”

“…As an example, noro virus infection was observed in patients with LRBA deficiency who received abatacept . Therefore, the evaluation of past and current infections before the targeted therapies and the careful monitoring of EBV and CMV are required …”

“…16 Therefore, the evaluation of past and current infections before the targeted therapies and the careful monitoring of EBV and CMV are required. 5,95 HSCT has been conducted as a treatment option for lifethreatening, treatment-resistant manifestations in patients with CTLA-4 insufficiency. 86 Schwab et al 5 reported that 12 of 90 affected CTLA4 mutation carriers underwent HSCT between 10 and 50 years of age, due to uncontrollable cytopenia, enteropathy, and lymphoma with additional autoimmune disorders involving lymphoproliferative and infectious complications.…”