Krishnarajah, S. | 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↗

bioRxiv2024

Regulatory T cells control type 1-driven immunopathology restraining GM-CSF-producing helper T cells

Regulatory T (Treg) cells are critical for maintaining peripheral tolerance and preventing autoimmunity. Treg cell depletion or dysfunction rapidly results in fatal multiorgan inflammation linked to unrestrained effector T cell expansion, but the cytokine network underlying immunopathology, and its direct cellular mediators, remain elusive. Here, we combined gene targeting, fate-mapping tools, and high-dimensional cytometry to identify the T helper (TH) cell-derived cytokines and responding cells that execute inflammatory tissue damage upon global loss of peripheral tolerance in mice. We found that TH cell-derived GM-CSF, but not IL-17A, directed the ensuing immunopathology and thereby mortality through recruitment of tissue-invading phagocytes and granulocytes, and enhancement of their reactive oxygen species production and phagocytic proficiency. Our study highlights the critical role of Treg cells in controlling GM-CSF- producing TH cells and type 1-responses to restrain phagocyte-mediated tissue destruction and provides a framework for the use of anti-GM-CSF therapies in patients with chronic inflammatory disorders.

immunology↗