Wijnen, S. | Search bioRxiv

bioRxiv2026

SIGLEC1 FACILITATES MACROPHAGE-CD8+ T CELL INTERACTIONS AND CORRELATES WITH CANCER IMMUNOTHERAPY RESPONSE

Antigen-presenting cell (APC) interactions with cytotoxic T cells are critical for anti-tumour immunity and response to immune checkpoint blockade (ICB), yet context-specific regulators in the tumour microenvironment remain not fully defined. Here we identify the lectin receptor SIGLEC1 as a key mediator of macrophage-T cell interactions in human melanoma. In a well-characterized patient cohort, SIGLEC1 was selectively upregulated in inflammatory macrophages physically associated with activated/exhausted CD8 T cells. Imaging and functional analyses revealed that SIGLEC1 accumulates at the macrophage-T cell interface and promotes cell clustering. SIGLEC1 ligands were enriched on activated T cells, and their blockade reduced cytotoxic cytokine production ex vivo. Single-cell (spatial) transcriptomics across independent ICB-treated melanoma cohorts showed that SIGLEC1 macrophages localize near CD8 T cells and are enriched in responders, where they also associate with T cells expressing activation/exhaustion markers. These findings define a SIGLEC1-dependent macrophage-T cell niche linked to effective immunotherapy.

immunology↗

bioRxiv2026

CMAS dampens anti-tumor immunity and associates with response to neoadjuvant immunotherapy in melanoma

Identifying immune-regulatory pathways to predict response is crucial for the efficacy of immune checkpoint blockade (ICB) immunotherapies. Sialylation is upregulated in tumor cells and modulates immune responses in cancer, yet its impact on patient clinical outcome and the spatial organization of the tumor microenvironment remain unclear. Here, using publicly available single-cell RNA sequencing data we show that expression of the sialylation master regulator CMAS in melanoma cells correlates with poorer patient survival. Using a murine melanoma model, we demonstrate that Cmas deletion in tumor cells severely impaired tumor growth and improved anti-tumor lymphoid and myeloid cell responses, increasing tumor cell-intrinsic susceptibility to interferon-gamma-, CD4+ T cell-, and macrophage-mediated killing. Single-cell spatial transcriptomics on neoadjuvant ICB-treated melanoma patient tumor biopsies revealed that CMAS expression in tumor cells inversely correlated with tumor cell proximity to and activation status of T cells and macrophages. Furthermore, expression of CMAS in tumor cells was increased in patients who did not respond to immunotherapy, compared to responders. Overall, our work identifies CMAS as a key modulator of tumor-immune dynamics associated with survival and response to neoadjuvant ICB immunotherapy in melanoma patients.

cancer biology↗