HIGH-THROUGHPUT PROFILING OF INNATE IMMUNE CELLS TO UNVEIL TUMOR ESCAPE MECHANISMS IN MATCHED COLORECTAL CANCER AND LIVER METASTASES
type: CreativeWork
description: Colorectal cancer (CRC) represents one of the leading global health burdens, with the liver being its predominant site of distant metastasis. A significant proportion of patients with colorectal liver metastases (CRLM) are diagnosed with synchronous lesions (sCRLM), identified at or shortly after diagnosis of the primary tumor, a clinical scenario linked to aggressive disease and poor outcomes. A major clinical challenge in this setting is that the majority of CRCs with liver metastasis are microsatellite stable or low instable (MSS or MSI-L, respectively), tumor types largely unresponsive to immune checkpoint (IC) therapies. Indeed, MSS/MSI-L tumors display "immune cold" microenvironments dominated by immunosuppressive mechanisms, which severely constrain treatment options. This unmet clinical need highlights the importance of dissecting the immune microenvironment of sCRLM, to identify early drivers of metastatic progression and highlight immunological features with therapeutic potential, ultimately supporting a new immune-weighted stratification of patients for novel therapeutic approaches. To this end, we combined single-cell transcriptomic with paired V(D)J profiling to generate a multi-compartmental innate immune map of synchronous CRC and matched sCRLM, together with circulating blood samples. Our analyses revealed that Tumor-Associated Macrophages (TAMs) and Dendritic Cells (DCs) emerged as dominant players of the tumor microenvironment (TME) along divergent tumor-specific trajectories. In CRC, TAMs were enriched in inflammatory states that paradoxically supported immune activation while simultaneously laying the groundwork for metastatic dissemination. Conversely, CRLM was dominated by proliferative CTLA4high immunoregulatory TAMs, whose higher frequencies were associated with shorter disease-free survival and worse prognosis. Furthermore, we identified two CRLM-specific TAM subsets characterized by IL7R expression and a cytotoxic/NK-like signature, suggest…
abstract: Colorectal cancer (CRC) represents one of the leading global health burdens, with the liver being its predominant site of distant metastasis. A significant proportion of patients with colorectal liver metastases (CRLM) are diagnosed with synchronous lesions (sCRLM), identified at or shortly after diagnosis of the primary tumor, a clinical scenario linked to aggressive disease and poor outcomes. A major clinical challenge in this setting is that the majority of CRCs with liver metastasis are microsatellite stable or low instable (MSS or MSI-L, respectively), tumor types largely unresponsive to immune checkpoint (IC) therapies. Indeed, MSS/MSI-L tumors display "immune cold" microenvironments dominated by immunosuppressive mechanisms, which severely constrain treatment options. This unmet clinical need highlights the importance of dissecting the immune microenvironment of sCRLM, to identify early drivers of metastatic progression and highlight immunological features with therapeutic potential, ultimately supporting a new immune-weighted stratification of patients for novel therapeutic approaches. To this end, we combined single-cell transcriptomic with paired V(D)J profiling to generate a multi-compartmental innate immune map of synchronous CRC and matched sCRLM, together with circulating blood samples. Our analyses revealed that Tumor-Associated Macrophages (TAMs) and Dendritic Cells (DCs) emerged as dominant players of the tumor microenvironment (TME) along divergent tumor-specific trajectories. In CRC, TAMs were enriched in inflammatory states that paradoxically supported immune activation while simultaneously laying the groundwork for metastatic dissemination. Conversely, CRLM was dominated by proliferative CTLA4high immunoregulatory TAMs, whose higher frequencies were associated with shorter disease-free survival and worse prognosis. Furthermore, we identified two CRLM-specific TAM subsets characterized by IL7R expression and a cytotoxic/NK-like signature, suggest…
author: MARZANO, PAOLO
language: eng
keywords: CRC, CRLM, scRNA-seq, scTCR-seq, TAM, γδ T cell, NK cells, Settore MEDS-26/A - Scienze tecniche di medicina di laboratorio
date published: 2026-01-27
date modified: 2026-07-27T20:19:08Z
provider: Università degli Studi di Milano
publisher: Networked Digital Library of Theses and Dissertations
type: WebPage
source organization: Università degli Studi di Milano

PropertyValue
property ID: Handle
value: https://hdl.handle.net/2434/1204983