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JAK inhibitors alleviate EGFRi-induced diarrhea by protecting intestinal stem cells from adaptive immune- exacerbated injury

ABSTRACT: While intestinal stem cells (ISCs) are essential for epithelial homeostasis, their dynamic regulation during immune-mediated injury remains undefined. Jejunal intestinal stem cell (ISC) proliferative suppression emerges as a pathological hallmark of oral EGFR tyrosine kinase inhibitors (TKIs), propelling chemokine-directed migration of T/B lymphocytes from Peyer's patches. Genetic ablation of adaptive immunity reversed ISC suppression and accelerated mucosal repair. Spatial transcriptomics revealed enhanced ISC-adaptive immune cell crosstalk in the jejunum. Ex vivo modeling demonstrated activated T cells directly impair ISC survival through IFN-γ and TNF-α, with JAK/STAT signaling constituting the critical downstream effector. Targeted JAK inhibition prevented T/B cell-mediated pathology while exhibiting dual efficacy: mitigating EGFRi–induced diarrhea without substantially compromising antitumor efficacy. This work redefines TKI-induced enteropathy as an immune-driven pathology and identifies JAK inhibition as the first mechanism-based supportive therapy, establishing a paradigm for precision management of targeted therapy toxicities.

ORGANISM(S): Mus Musculus

SUBMITTER: Shiyi Zhang

PROVIDER: PXD066986 | iProX | Wed Aug 06 00:00:00 BST 2025

REPOSITORIES: iProX

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Project description:Patients with the microsatellite stable (MSS) subset of colorectal cancer, which accounts for 85-90% of all human colorectal cancer cases, do not respond to PD-(L)1 immune checkpoint inhibitor immunotherapy. Metastasis accounts for over 90% of human colorectal cancer mortality and liver metastasis accounts for 90% of human colorectal cancer metastasis. The mechanism underlying colorectal tumor cell immune evasion and the resultant liver metastasis is incompletely understood. The SUV39H1-H3K9me3 epigenetic pathway has emerged as a key regulator of CTL persistence and effector function in anti-tumor immunity. We therefore aimed at testing the hypothesis that H3K9me3 induces CTL dysfunction to promote colorectal tumor liver metastasis. Using a mouse MSS colon tumor experimental liver metastasis model, we observed that PD-1 blockade immunotherapy does not induce CTL activation in the liver metastases and exhibits no significant efficacy in suppression of liver metastasis. CTL adaptive transfer increased accumulation of the tumor-specific CTLs in liver metastases but also exhibited no significant efficacy in suppression of liver metastasis. However, pharmacological inhibition of H3K9me3-specific histone methyltransferases with the small molecule F5446 significantly suppressed liver metastasis in mice. scRNA-seq analysis of liver metastases-infiltrating immune cells revealed that F5446 therapy does not increased total level of T cell tumor infiltration. Instead, inhibition of H3K9me3 increased Tex and decreased Tcm in liver metastases. Analysis of human colon tumor scRNA-Seq datasets identified Tex, Tcm and Tem-like clusters in both primary and liver metastasis with higher level of Tex subset of T cells in liver metastases than primary tumor. Our findings determine that colon tumor cells induce H3K9me3 to regulate T cell differentiation and effector function in liver metastases microenvironment and targeting H3K9me3 is a promising approach for suppression of CRC liver metastasis.

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JAK inhibitors alleviate EGFRi-induced diarrhea by protecting intestinal stem cells from adaptive immune- exacerbated injury

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