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Modulation of Immune Checkpoints by Chemotherapy in Human Colorectal Liver Metastases

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) cance...

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Detalles Bibliográficos
Autores principales: Jabbari, Neda, Kenerson, Heidi L., Lausted, Christopher, Yan, Xiaowei, Meng, Changting, Sullivan, Kevin M., Baloni, Priyanka, Bergey, Dani, Pillarisetty, Venu G., Hood, Leroy E., Yeung, Raymond S., Tian, Qiang
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Elsevier 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7762777/
https://www.ncbi.nlm.nih.gov/pubmed/33377131
http://dx.doi.org/10.1016/j.xcrm.2020.100160
Descripción
Sumario: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.