Guido Vinzoni, E. | Search bioRxiv

bioRxiv2025

Memory CD4 T cells orchestrate neoadjuvant-responsive niches in colorectal cancer liver metastases

Colorectal cancer frequently progresses to liver metastases (CRLM), a stage with limited treatment options and poor prognosis. Neoadjuvant chemotherapy is used to control tumor growth and enable resection, yet many patients fail to respond, and the mechanisms underlying this variability remain unclear. To identify determinants of treatment response, we profiled T cell states and their spatial organization in CRLM. We found that spatial arrangement and polarization of CD4 memory T cell networks determine treatment outcome. In responders, Th1-like CD4 memory T cells organized with effector-memory CD8 T cells and antigen-presenting cells (APCs) into therapy-responsive immune niches (TRINs) that support CD4-mediated APC licensing and local immune engagement. Non-responders lacked such immune architecture, exhibiting myeloid-rich regions dominated by circulating-like CD4 memory and regulatory T cells. CD4-driven TRINs thus emerge as key determinants of chemotherapy efficacy and provide a rationale for developing biomarkers and strategies that enhance CD4-APC-CD8 crosstalk within organized immune niches. Statement of significanceTh1-polarized CD4 memory T cells form therapy-responsive immune niches (TRINs) that orchestrate CD4, CD8, and APC function in colorectal cancer liver metastases, a clinically challenging and immunologically cold tumor type. TRINs define chemotherapy response and provide a mechanistic foundation for biomarker development and immunotherapy strategies designed to restore anti-tumor immunity.

immunology↗

bioRxiv2023

In vivo screening of tumor-hepatocyte interactions identifies Plexin B2 as a gatekeeper of liver metastasis

It is estimated that only 0.02% of disseminated tumor cells are able to seed overt metastases1. While this indicates the presence of environmental constraints to metastatic seeding, the landscape of host factors controlling this process remains largely unknown. Combining transposon technology2 and fluorescent niche labeling3, we developed an in vivo CRISPR activation screen to systematically investigate the influence of hepatocytes on metastatic seeding in the liver. Our approach enabled the identification of Plexin B2 as a critical host-derived regulator of metastasis. Plexin B2 upregulation in hepatocytes dramatically enhances grafting in colorectal and pancreatic cancer syngeneic models, and promotes seeding and survival of patient-derived organoids. Notably, ablation of Plexin B2 in hepatocytes prevents mesenchymal-to-epithelial transition of extravasated tumor cells and thereby almost entirely suppresses liver metastasis. We dissect a mechanism by which Plexin B2 interacts with class 4 semaphorins on tumor cells, activating Rac1 signaling and actin cytoskeleton remodeling, thereby promoting the acquisition of epithelial traits. Our findings highlight the essential role of signals from the liver parenchyma for the survival of disseminated tumor cells, prior to the establishment of a growth promoting niche. They further suggest that acquisition of epithelial traits is required for the adaptation of extravasated cells to their new tissue environment. Targeting of Plexin B2 on hepatocytes shields the liver from colonizing cells and thus presents an innovative therapeutic strategy for preventing metastasis. Finally, our screening technology, which evaluates host-derived extrinsic signals rather than tumor-intrinsic factors for their ability to promote metastatic seeding, is broadly applicable and lays a framework for the screening of environmental constraints on metastasis in other organs and cancer types.

cancer biology↗