Prognostic value of host genetic variants determining Bifidobacterium abundance in the lactose metabolism pathway for immunotherapy efficacy.

Abstract

2651 Background: The potential predicative and therapeutic value of Bifidobacterium in immune checkpoint inhibitors (ICIs) treatment has been widely studied. However, the value of its genetic determinants on the prognosis of ICIs treatment remains unclear. Methods: we examined the associations of 11 single nucleotide polymorphisms (SNPs) located at host genes determining Bifidobacterium abundance with the outcomes of ICIs treatment in 370 eligible cancer patients. Results: Cox regression analysis revealed that rs3739020 TT carriers experienced significantly extended OS ( P -value = 0.003, adjusted HR = 0.46, 95%CI = 0.27-0.77) compared with GG+TG carriers. The LCT haplotype analysis showed that the lactose poor metabolizers exhibited significantly poorer OS ( P -value = 0.002, adjusted HR = 0.45, 95%CI = 0.27-0.74) than the extensive or intermediate metabolizers. In polygenic SNP analysis, the high galactose level carriers exhibited significantly prolonged OS ( P -value = 0.007, adjusted HR = 0.32, 95%CI = 0.14-0.73) and progression-free survival (PFS, P -value = 0.001, adjusted HR = 0.45, 95%CI = 0.29-0.71). All the four SNPs and the LCT metabolic phenotype were not associated with the occurrence of overall immune-related adverse events (irAEs). Genetically predicted Bifidobacterium abundance was significantly associated with an increased abundance of lactose metabolism pathway ( P -value = 0.012, Beta coefficient = 0.549). Conclusions: SNPs determining Bifidobacterium abundance in the lactose metabolism pathway have prognostic value for immunotherapy efficacy, and the lactose extensive and intermediate metabolizers exhibited better immunotherapy efficacy. The details of LCT metabolic phenotypes and the associations of LCT metabolic phenotypes with overall survival. LCT genotypes and their risk allele rs3739020G rs56263017C rs55809728A rs3739022A HR P Lactose extensive metabolizer (EM, no risk allele exist) TT TT GG GG Refernces Lactose inermediate metabolizer (IM, risk alleles exist in 1-3 SNPs) TG or GG TT GG GG 0.58,95%CI=0.33-0.99 0.049 TT TC or CC GG GG TT TT AA or GA GG TG or GG TT GG AA or GA TG or GG TC or CC GG GG TG or GG TT AA or GA GG TT TT GG AA or GA TT TC or CC AA or GA GG TT TC or CC GG AA or GA TG or GG TT AA or GA AA or GA TG or GG TC or CC AA or GA GG TG or GG TC or CC GG AA or GA TT TT AA or GA AA or GA TG or GG TC or CC AA or GA AA or GA Lactose poor metabolizer (PM, risk alleles exist in 4 SNPs) TG or GG TC or CC AA or GA AA or GA 0.33,95%CI=0.18-0.62 0.001 The patients were stratified into three LCT metabolic phenotypes (PMs, IMs, EMs) according to the existence of the risk alleles (rs3739020 G, rs56263017 C, rs55809728 A, and rs3739022 A) in these four LCT/MCM6 SNPs.The lactose EMs and IMs exhibited significantly extended OS than PMs.