Modulation of Immune Checkpoints by Chemotherapy in Human Colorectal Liver Metastases
| Autor: | Leroy Hood, Venu G. Pillarisetty, Qiang Tian, Kevin M. Sullivan, Raymond S. Yeung, Christopher Lausted, Priyanka Baloni, Dani E Bergey, Xiaowei Yan, Changting Meng, Neda Jabbari, Heidi L. Kenerson |
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| Rok vydání: | 2020 |
| Předmět: |
PD-L1
Organoplatinum Compounds Colorectal cancer medicine.medical_treatment Programmed Cell Death 1 Receptor immune microenvironment colorectal cancer Irinotecan chemotherapy General Biochemistry Genetics and Molecular Biology Article galectin-9 Immune system Antineoplastic Combined Chemotherapy Protocols medicine Tumor Microenvironment Humans single-cell analysis Neoplasm Metastasis Hepatitis A Virus Cellular Receptor 2 Chemotherapy biology business.industry Liver Neoplasms single-cell transcriptome medicine.disease Immune checkpoint digestive system diseases Oxaliplatin Blockade organotypic culture Cancer research biology.protein Camptothecin business Colorectal Neoplasms liver metastases TIM3 medicine.drug |
| Zdroj: | Cell Reports Medicine |
| ISSN: | 2666-3791 |
| Popis: | Summary 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. Graphical Abstract Highlights CRLM slice culture can assess immune response to chemotherapy Single-cell analysis identifies cancer subtypes with differing response to chemotherapy 5-FU+irinotecan modulates interferon and PD-L1 pathways in stem-like CRLM Combining chemotherapy with TIM-3 blockade is synergistic in enterocyte-like CRLM The response of colorectal liver metastases (CRLM) to chemotherapy is analyzed in 3D organotypic tumor slices by single-cell RNA-seq. Jabbari et al. find two subtypes (stem-like and enterocyte-like) of CRLM that express different immune checkpoint ligands and respond differently to chemotherapy. The study highlights the chemomodulation of the tumor immune microenvironment that can be targeted therapeutically. |
| Databáze: | OpenAIRE |
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