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) 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. [Display omitted] CRLM slice culture can assess immune response to chemotherapySingle-cell analysis identifies cancer subtypes with differing response to chemotherapy5-FU+irinotecan modulates interferon and PD-L1 pathways in stem-like CRLMCombining 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.