Immune checkpoint inhibitor (ICI) treatment could bring long-lasting clinical benefits to patients with metastatic cancer. However, only a small proportion of patients respond to PD-1/PD-L1 blockade, so predictive biomarkers are needed. Here, based on DNA methylation profiles and the objective response rates (ORRs) of PD-1/PD-L1 inhibition therapy, we identified 269 CpG sites and developed an initial CpG-based model by Lasso to predict ORRs. Notably, as measured by the area under the receiver operating characteristic curve (AUC), our model can produce better performance (AUC = 0.92) than both a model based on tumor mutational burden (TMB) (AUC = 0.77) and a previously reported TMB model (AUC = 0.71). In addition, most CpGs also have additional synergies with TMB, which can achieve a higher prediction accuracy when joined with TMB. Furthermore, we identified CpGs that are associated with TMB at the individual level. DNA methylation modules defined by protein networks, Kyoto Encylopedia of Genes and Genomes (KEGG) pathways, and ligand-receptor gene pairs are also associated with ORRs. This method suggested novel immuno-oncology targets that might be beneficial when combined with PD-1/PD-L1 blockade. Thus, DNA methylation studies might hold great potential for individualized PD1/PD-L1 blockade or combinatory therapy.

No abstract

Background: NOTCH pathway, a highly conserved signaling system, is regulated by short-range cell-cell interaction between NOTCH receptor (NOTCH1-4) and “canonical” ligand, or non-canonically through activation of other pathways. Previous research on the NOTCH gene revealed that NOTCH signaling is associated with tumorigenesis, mutagenesis, and immune tolerance in several tumors, indicating its association with the clinical benefit of immune checkpoint inhibitors (ICIs). However, the NOTCH characteristics, its correlation with immunogenic marker, and the predictive value of immunotherapy in colorectal cancer (CRC) was unknown. Methods: An independent cohort (the MSKCC study cohort) with next-generation sequencing (NGS) data from 109 patients with CRC of pan-cancer, were used to analyze the prognostic effect of NOTCH1-4 on immunotherapy. Tumor tissue samples from Chinese head and neck cancer were analyzed using NGS (panel on 381/733-gene). TMB was defined as the total number of somatic non-synonymous mutations in coding region. MSI was evaluated by NGS of 500 known MSI loci. PD-L1 expression was evaluated using immunohistochemistry (Dako 22C3). Result: In the MSKCC cohort, there were 49 (45.0%) patients harbored NOTCH mutation(NOTCHmut), including 16 (14.7%) patients of NOTCH1, 7 (6.4%) patients of NOTCH2, 16 (14.7%) patients of NOTCH3, and 10 (10.9%) patients of NOTCH4. NOTCH1 mutation (median, 65.4 Muts/Mb) was associated with higher TMB (P<0.001) than NOTCH1 wild-type (NOTCHwt) (median, 6.8 Muts/Mb), same as NOTCH2 (median, 61.4 Muts/Mb vs 7.8 Muts/Mb; P<0.001), NOTCH3 (median, 64.9 Muts/Mb vs 6.8 Muts/Mb; P<0.001), and NOTCH4 (median, 76.7 Muts/Mb vs 7.8 Muts/Mb; P<0.001). In terms of prognostic effect, there was significant difference on overall survival (OS) (HR = 0.17, P=0.008) between NOTCH3mut (median, 11.5 months) and NOTCH3wt (median, 8 months), but there was no difference in others of NOTCH. In Chinese patients, genetic mutation of 1166 CRC patients were analyzed using NGS, of which 157 (13.5%) harbored NOTCH mutation, including NOTCH1 (123, 10.5%), NOTCH2 (221, 18.9%), NOTCH3 (135, 11.6%), and NOTCH4 (55, 4.7%). NOTCH3mut (median, 47,5 Muts/Mb) was associated with higher TMB (P<0.001) than NOTCH3wt (median, 7.3 Muts/Mb), which was significant difference, same as the other three. For the TMB, there was also significant difference in MSI between NOTCH1-4mut and NOTCH1-4wt (all of the four P<0.001). There was significant difference in PD-L1 expression between NOTCHwt with NOTCH1mut (P =0.005) and NOTCH2mut (P<0.001), but not with NOTCH3mut and NOTCH4mut. Conclusions: The results showed that the NOTCH genes had a high correlation with TMB and MSI in CRC, and the NOTCH3 might a potential biomarker for immune checkpoint therapy. Citation Format: Xiyu Yuan, Xue Hu, Yating Zheng, Mengli Huang. Investigation of NOTCH mutation and correlation with immunotherapy biomarker in Chinese colorectal cancer patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5095.