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Author Spotlight: Investigating Immune Cell Dynamics in the Tumor Microenvironment — Challenges and Innovations in Cancer Prognosis
Published on: April 12, 2024
KRAS Withdrawal in Cholangiocarcinoma Leads to Immune Infiltration and Tumor Regression
Youwei Qiao1, Matthew F Yee1, Chaitanya N Parikh2
1RNA Therapeutics Institute, University of Massachusetts Chan Medical School, Worcester, MA, 01605, USA.
Abstract:
Cholangiocarcinoma (CCA) is a liver cancer subtype with poor survival rates. KRAS mutations are found in 15-40% of CCA, representing a new potential treatment target. Whether KRAS inhibition leads to CCA tumor regression is unknown, partly due to the lack of conditional animal models. A conditional TRE.KrasG12D/Trp53 knock-out (TKP) CCA mouse model is engineered using the transposon system and CRISPR-Cas9. Withdrawal of KrasG12D results in >90% tumor regression by day 7, accompanied by infiltration and enrichment of activated CD8+ T cells, shown by IHC, co-IF staining, and single-cell RNA-Seq. Bulk RNA-Seq of TKP cell line suggested that KrasG12D withdrawal stimulates the transforming growth factor beta pathway and induces senescence. Cytokine array characterizes the secretion of pro-inflammatory factors, including IL-15 and CCL17. Lentiviral overexpression of murine IL-15 and CCL17 delays CCA tumor progression in a syngeneic transplant model. Consistently, expression of IL-15 resulted in blockade of tumor progression in the TKP CCA model. These findings highlight the importance of oncogenic Kras in CCA tumor maintenance and underscore KRAS inhibition as a potential therapeutic approach for CCA.
Insights
KRAS inhibition effectively regresses cholangiocarcinoma (CCA) tumors in a novel mouse model. This regression involves CD8+ T cell infiltration and is associated with IL-15 and CCL17 secretion, suggesting therapeutic potential.
Area of Science:
- Oncology
- Cancer Biology
- Immunology
Background:
- Cholangiocarcinoma (CCA) is an aggressive liver cancer with poor prognosis.
- KRAS mutations are prevalent in CCA, presenting a potential therapeutic target.
- Lack of conditional models hinders investigation into KRAS inhibition effects on CCA.
Purpose of the Study:
- To engineer a conditional mouse model for studying KRAS-driven CCA.
- To investigate the effects of KRAS inhibition on CCA tumor regression and the tumor microenvironment.
- To identify molecular mechanisms and potential therapeutic targets associated with KRAS inhibition in CCA.
Main Methods:
- Engineered a conditional TRE.KrasG12D/Trp53 knock-out (TKP) CCA mouse model using transposon and CRISPR-Cas9 systems.
- Analyzed tumor regression, CD8+ T cell infiltration (IHC, co-IF, scRNA-Seq), and gene expression changes (bulk RNA-Seq) upon KrasG12D withdrawal.
- Utilized cytokine arrays and lentiviral overexpression to assess the role of secreted factors like IL-15 and CCL17.
Main Results:
- >90% CCA tumor regression observed within 7 days of KrasG12D withdrawal.
- Tumor regression was accompanied by significant infiltration and enrichment of activated CD8+ T cells.
- KrasG12D withdrawal induced TGF-beta pathway activation, senescence, and secretion of IL-15 and CCL17.
- Overexpression of IL-15 and CCL17 delayed CCA tumor progression in vivo, with IL-15 blocking tumor progression in the TKP model.
Conclusions:
- Oncogenic KRAS is crucial for maintaining CCA tumor growth.
- KRAS inhibition triggers anti-tumor immune responses, particularly involving CD8+ T cells.
- IL-15 and CCL17 are key secreted factors mediating tumor regression and may serve as therapeutic targets for CCA.
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