Dual Transcriptional Drivers of Immune Suppression in SACC: NOTCH1 for Cellular and MYB for Humoral Immunity
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Salivary adenoid cystic carcinoma (SACC) exemplifies immunologically cold tumors, yet the mechanisms remaining largely confined to tumor cell-intrinsic functions. Our RNA sequencing analysis uncovered systemic immune dysregulation in SACC patients, characterized by hematopoietic stem cell (HSC) suppression, elevated immature B-cell proportion, effector T-cell depletion, and compensatory myeloid expansion. Notably, lung metastases exhibited a relatively “hotter” immune milieu driven by the presence of tissue-resident T cells, yet remained characterized by a predominant accumulation of immature B cells. Mechanistically, cancer stem cells (CSCs) acquired a progenitor phenotype co-expressing G2M and common lymphoid progenitor (CLP) markers. Sustained OLIGI/NOTCH1 signaling within these progenitors impaired dendritic progenitors’ differentiation and masked tumor antigens. MYB collaborated with NOTCH1 / CXCL13/CXCR5 signaling to restrict B-cell maturation in metastases. Crucially, CSC-derived IL17RB signaling directly activated NOTCH1 , driving immune suppression. These findings establish bone marrow dysfunction as a core mechanism, advocating IL17RB- or bone marrow-targeted strategies for treating SACC immune coldness.
Significance
Our novel transcriptomic analysis revealed a key G2M/CLP dual-progenitor state in SACC immunocold tumors. Tracing its origin to hematopoietic differentiation, we uncovered a NOTCH1 -mediated dual-hit mechanism: restricting antigen presentation to silence T cells while partnering with MYB to block B-cell maturation. This finding pinpoints a root cause of immune evasion and establishes this pathway as a central therapeutic target.
Graphical Abstract