Abstract 1989P
Background
The administration of immune checkpoint inhibitors is a breakthrough to the traditional carcinoma regimen in contemporary era. Recently, Supplemental Biologics License Application (sBLA) accepted for KEYTRUDA monotherapy in patients whose tumors are TMB-high who have progressed following prior treatment. However, the mechanisms of TMB-Low leading to poor efficacy of tumor immunotherapy is still unclear.
Methods
In clinical cohort, genomic profiling of DNA was performed using NGS method. In TCGA cohort, the relevant clinicopathological and WES data were download. The TMB was defined as the numbers of SNVs including synonymous, nonsynonymous mutations, and InDels per megabases in coding regions of sequenced genome, TMB >10/MB and < 10/MB were defined as TMB-H and TMB-L group.
Results
In clinical cohort, the frequency of TMB-H >10/MB in stomach cancer, cervical cancer, esophageal cancer and lung cancer were 14.8%, 17.6%, 13.4%, and 13.7%, respectively. Meanwhile, the frequency of TMB-H >10/MB in TCGA cohort were 26.7%, 22.4%, 20.8%, and 46.3%, respectively. We further analyzed different expression genes between TMB-H ≥10/MB and < 10/MB groups in these cancers. SCGB1A1, an important regulatory gene for the proliferation of interleukin-4,5,13, was significantly downregulated (decreased by 62.1%, p<0.001 in stomach cancer; 23.7%, p<0.001 in cervical cancer; 15.6%, p=0.027 in esophageal cancer and 11.7%, p=0.013 in lung cancer) in TMB< 10/MB group. Besides, IL36A, an important regulatory gene for the proliferation of interleukin-6, was also significantly downregulated (decreased by 72.3%, p<0.001 in stomach cancer; 40.2%, p<0.001 in cervical cancer; 56.8%, p=0.007 in esophageal cancer and 13.1%, p=0.043 in lung cancer) in TMB< 10/MB group.
Conclusions
In our study, the frequency of TMB-H ≥10/MB and the mechanism of TMB in immunotherapy were investigated in clinical and TCGA cohort, which might provide useful information to guide precisely application of PD-1 or PD-L1 inhibitors. Besides, down-regulation of SCGB1A1 and IL36A may serve as mechanisms of TMB-Low leading to poor efficacy of immunotherapy.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
The authors.
Funding
Has not received any funding.
Disclosure
All authors have declared no conflicts of interest.