Age, sex, and specific gene mutations affect the effects of immune checkpoint inhibitors in colorectal cancer

Abstract

The effect of age and sex on the predictive value of colorectal cancer (CRC) patients treated with immune checkpoint inhibitors (ICIs) has been controversial, and the effect of specific gene mutations on the predictive value of CRC patients treated with ICIs remains to be explored. Our study analyzed the influence of the above factors on the overall survival (OS) of CRC patients receiving ICIs and explored the influencing mechanism of various predictive biomakers. We performed survival prognostic correlation analysis and bioinformatics analysis on the clinical CRC cohort receiving ICIs in from the Memorial Sloan Kettering Cancer Center (MSKCC) and the clinical and genetic data from The Cancer Genome Atlas (TCGA)-CRC dataset, including immunogenicity analysis, tumor immune microenvironment analysis, and gene set enrichment analysis and so on. We found that mutation count >11 mutation/Mb (tumor mutation burden, TMB-high) (HR = 0.22, 95 %CI: 0.09−0.53; P < 0.001), male (HR = 0.51, 95 %CI: 0.28−0.93; P = 0.029), RNF43-mutant (MT) (HR = 0.12, 95 %CI: 0.03−0.49; P = 0.003), CREBBP-MT (HR = 0.23, 95 %CI: 0.07−0.76; P = 0.016), NOTCH3-MT (HR = 0.17, 95 %CI: 0.04−0.74; P = 0018), PTCH1-MT (HR = 0.27, 95 %CI: 0.08−0.9; P = 0.033), CIC-MT (HR = 0.23, 95 %CI: 0.05−0.93; P = 0.040), DNMT1-MT (HR = 0.12, 95 %CI: 0.02−0.93; P = 0.043) and SPEN-MT (HR = 0.31, 95 %CI: 0.09−0.99; P < 0.049) are all related to longer OS, but age≤65 years (HR = 3.01, 95 %CI: 1.18–7.65; P = 0.021), APC-MT (HR = 2.51, 95 %CI: 1.12–5.63; P = 0.026) and TP53-MT (HR = 1.94, 95 %CI: 1.03–3.65; P = 0.041) are associated with shorter OS. The reason why positive predictive markers provide survival benefits to CRC may be related to higher immunogenicity such as TMB, highly expression of mRNA related to immune response, highly infiltrating immune-active cells such as CD8 + T cells, active immune-active pathways, and DNA damage repair pathways with an increased number of mutations.