Abstract 5144: The potential biomarkers and rational combination of immunotherapy in microsatellite stable colorectal cancer

Abstract

Abstract Purpose Immune checkpoint blockades (ICBs) have been reported to be used in early stage colorectal cancer (CRC) as neoadjuvant therapy. However, it seems that microsatellite stable (MSS) CRC patients obtained no significant clinical benefit in studies with small sample size. We aimed to explore the potential biomarkers and rational immunotherapy to optimize response to ICBs in MSS CRC. Procedures Whole exome sequencing and RNAseq of 612 CRC patients from The Cancer Genome Atlas were analyzed. T cell dysfunction/exclusion signatures and Tumor infiltrating lymphocytes were calculated from TIDE model and TIMER algorithm, respectively. Mann Whitney U test and Kruskal test were used to compare the difference among two or more than two groups. P value was adjusted by BH method for multiple comparisons. Results There were 109 stage I, 228 stage II, 184 stage III and 91 stage IV in 612 CRC patients. The MSI-H prevalence, tumor mutation burden, PD-L1 mRNA and CD8 T cell infiltration decreased with the increase in pathologic stage (all P < 0.01). In MSS CRC, mRNA expression of immune checkpoint related genes including PD-L1, CTLA4 and LAG3 were significantly higher in stage I-III than stage IV (adjusted P < 0.01, < 0.01 and 0.04, respectively). For immune activation genes (CD8A, CXCL9, CXCL10, GBP1, GZMB, GZMA, IFNG, FAS, STAT1, TAP1), their mRNA expression levels increased with the decrease of stage (All adjusted P < 0.01). Besides, stage I-III MSS CRC had lower T cell exclusion signature score than stage IV (adjusted P = 0.02). No similar results were observed in MSI-H. Compared with MSI-H, MSS had higher M2 macrophage signature score (P < 0.001), but no association were observed between M2 macrophage signature and stage. Conclusions Early stage CRC with MSS had higher levels of positive predictive features for ICBs treatment, which suggested stronger immune responsiveness. Combination of M2 macrophage inhibitor and ICBs has the potential to turn “cold tumor” into “hot tumor” and acts as a promising therapeutic regimen, especially for early stage CRC. More clinical trials are needed to confirm this hypothesis. Note: This abstract was not presented at the meeting. Citation Format: Xuman Lu, Zhe Ji, Jing Zhao, Yuzi Zhang, Mengli Huang, Shangli Cai, Jun Huang. The potential biomarkers and rational combination of immunotherapy in microsatellite stable colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 5144.