Cell Rep Med
washington; seattle; ISB
Metastatic colorectal cancer (CRC) is a major cause of cancer-related death, and incidence is rising in younger populations (younger than 50 years). Current chemotherapies can achieve response rates above 50%, but immunotherapies have limited value for patients with microsatellite-stable (MSS) cancers. The present study investigates the impact of chemotherapy on the tumor immune microenvironment. We treat human liver metastases slices with 5-fluorouracil (5-FU) plus either irinotecan or oxaliplatin, then perform single-cell transcriptome analyses. Results from eight cases reveal two cellular subtypes with divergent responses to chemotherapy. Susceptible tumors are characterized by a stemness signature, an activated interferon pathway, and suppression of PD-1 ligands in response to 5-FU+irinotecan. Conversely, immune checkpoint TIM-3 ligands are maintained or upregulated by chemotherapy in CRC with an enterocyte-like signature, and combining chemotherapy with TIM-3 blockade leads to synergistic tumor killing. Our analyses highlight chemomodulation of the immune microenvironment and provide a framework for combined chemo-immunotherapies.
Institute for Systems Biology
Jabbari, Neda; Kenerson, Heidi L; Lausted, Christopher; Yan, Xiaowei; Meng, Changting; Sullivan, Kevin M; Baloni, Priyanka; Bergey, Dani E; Pillarisetty, Venu G; Hood, Leroy; Yeung, Raymond S; and Tian, Qiang, "Modulation of Immune Checkpoints by Chemotherapy in Human Colorectal Liver Metastases." (2020). Articles, Abstracts, and Reports. 4345.