Gut microbiome immaturity and childhood acute lymphoblastic leukaemia.

Acute lymphoblastic leukaemia (ALL) is the most common cancer of childhood. Here, we map emerging evidence suggesting that children with ALL at the time of diagnosis may have a delayed maturation of the gut microbiome compared with healthy children. This finding may be associated with early-life epidemiological factors previously identified as risk indicators for childhood ALL, including caesarean section birth, diminished breast feeding and paucity of social contacts. The consistently observed deficiency in short-chain fatty-acid-producing bacterial taxa in children with ALL has the potential to promote dysregulated immune responses and to, ultimately, increase the risk of transformation of preleukaemic clones in response to common infectious triggers. These data endorse the concept that a microbiome deficit in early life may contribute to the development of the major subtypes of childhood ALL and encourage the notion of risk-reducing microbiome-targeted intervention in the future.

Association of Serum Immunoglobulin Levels with Solid Cancer: A Systematic Review and Meta-analysis.

BACKGROUND: The nature of humoral immunity in carcinogenesis remains poorly understood. In this systematic review and meta-analysis, we aimed to evaluate the association of serum immunoglobulin classes with solid cancer and test our hypothesis that the immune escape of tumors is accompanied by dysregulated systemic immunoglobulin class-switching. METHODS: Following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, we systematically searched the Cochrane Library, Embase, and MEDLINE/PubMed databases for observational studies investigating the association between serum immunoglobulins (IgA, IgG, and IgM) and histologically confirmed diagnosis of solid cancer in adults. We selected case-control studies, including more than 20 cases, and those explicitly stating that no form of anticancer treatment was administered prior to immunoglobulin measurement. No eligible cohort studies were identified. The primary summary measure was the standardized mean difference (SMD) with 95% confidence intervals (CI) calculated using a random effects model. RESULTS: Pooling 11 eligible studies comparing serum IgA levels in 1,351 patients and 560 control subjects revealed a statistically significant SMD (1.50; 95% CI, 0.96-2.04). Nonsignificant SMDs were observed for the 14 selected studies investigating serum IgG [SMD, -0.02 (95% CI, -0.22 to 0.18)] and for the 10 studies reporting serum IgM [SMD, 0.11 (95% CI, -0.10 to 0.32)]. Substantial heterogeneity between studies was observed despite sensitivity analysis by immunoglobulin measurement method, control matching, type of cancer, stage of disease, and sequential study exclusion. CONCLUSIONS: Serum immunoglobulin levels in patients diagnosed with solid cancer might be skewed toward class-switching to IgA, possibly reflecting Th2-polarized immunity. IMPACT: Further combinatorial analyses of serum immunoglobulin isotypes alongside other immune parameters in databases and observational studies are warranted.

Serum immunoglobulin levels and the risk of bladder cancer in the AMORIS Cohort.

BACKGROUND: The anti-tumour T-cell response in bladder cancer has been shown to correlate with response to treatment and prognosis. However, little is known about the role of humoral immunity in this highly immunogenic human cancer, which is characterised by a high mutation-associated neoantigen load and a strong response to immunotherapy. In the present study, we interrogated the Swedish Apolipoprotein Mortality Risk Study (AMORIS) to explore the relationship between pre-diagnostic serum immunoglobulin levels and the risk of developing bladder cancer. METHODS: Our analysis included all AMORIS participants aged 20 years or older, who had all three major serum immunoglobulins (IgA, IgM, IgG) recorded at the same baseline measurement (n = 29,876). All participants were free from bladder cancer at the time of measurement. Samples were obtained between 1985-1996, with follow-up information until 2011. Multivariate Cox proportional hazards regression was used to investigate the association between bladder cancer risk and different levels of pre-diagnostic serum immunoglobulins. RESULTS: During a mean follow-up period of 15.31 years, 163 (0.5%) individuals were diagnosed with bladder cancer. Multivariate Cox regression showed an inverse association between pre-diagnostic serum IgM levels ≥ 1.4 g/L and bladder cancer risk compared to serum IgM levels < 1.4 g/L [HR: 0.68 (95% CI 0.45-1.03)]. Corresponding associations could not be established for serum IgA or IgG. CONCLUSION: Our findings implicate serum IgM in the pathogenesis of bladder cancer and suggest that the concept of humoral immune surveillance against cancer warrants further mechanistic investigation.