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Baseline tumor features and peripheral blood immune dynamics that underlie efficacy in MSS metastatic colorectal cancer treated with regorafenib, ipilimumab, and nivolumab

ABSTRACT: Microsatellite-stable metastatic colorectal cancer (MSS mCRC) remains resistant to conventional immunotherapies, yet in a phase I trial the combination of regorafenib, ipilimumab, and nivolumab (RIN) demonstrated a 27.6% overall response rate and a median overall survival of 20 months, particularly benefiting patients without liver metastases. Correlative studies of tumor biopsies from eight patients and peripheral blood samples from 29 patients revealed that good responders had a more immunogenic tumor microenvironment (TME) at baseline, with enhanced cellular proliferation, active DNA repair pathways, and elevated STING pathway expression, along with a Th1-skewed cytokine profile in peripheral blood. Poor responders exhibited dysregulated inflammation, vascular remodeling, and T cells showing pathogen-response gene signatures indicative of chronic inflammation; in those with liver metastases, T cells showed immune senescence and metabolic hyperactivation. After RIN therapy, good responders displayed increased TME immune cell infiltration, upregulation of immune-related genes, marked expansion of previously low-frequency TCR clones in CD8 T cells, heightened naive T cell proliferation, and activation of immune and metabolic pathways. Poor responders initially showed transient increases in bulk CD8 T cells, NK cells, Th1 cytokine production, and reduced exhaustion markers but did not sustain meaningful TCR repertoire expansion. These findings underscore the potential of RIN to reshape the immunological landscape of MSS mCRC by modulating both TME and systemic immunity, highlighting the importance of predictive biomarkers to guide personalized therapeutic strategies, particularly for overcoming resistance in liver metastases.

ORGANISM(S): Homo sapiens

PROVIDER: GSE289583 | GEO | 2026/02/01

REPOSITORIES: GEO

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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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Baseline tumor features and peripheral blood immune dynamics that underlie efficacy in MSS metastatic colorectal cancer treated with regorafenib, ipilimumab, and nivolumab

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