Dual Transcriptional Drivers of Immune Suppression in SACC: NOTCH1 for Cellular and MYB for Humoral Immunity

Abstract

As a classic immune-"cold" tumor, salivary adenoid cystic carcinoma (SACC) represents a significant clinical challenge. Through sequencing analyses, we identify profound systemic immune dysregulation in SACC, characterized by suppressed hematopoiesis, T-cell exhaustion, compensatory myelopoiesis, and an expanded immature B-cell compartment. While lung metastases exhibit a relatively immune-engaged microenvironment enriched in tissue-resident T cells, these sites remain dominated by immature B cells. Mechanistically, this hematopoietic dysfunction originates from direct disruption of tumor-derived signaling entering the circulation, supported by detection of the SACC-signature MYB-NFIB fusion gene in peripheral plasma and blood cells. At the molecular level, we discover that IL17RB/OLIG1/NOTCH1 signaling pathways engage in multicellular crosstalk via IL33 or TP53 to suppress T-cell activation in primary tumors. Moreover, at lung metastatic sites, the MYB/MYBL2-NOTCH1-CXCL13-CXCR5 axis is blocked through CD24 or IL17RB, thereby inhibiting B-cell maturation. Single-cell transcriptomic profiling further identifies cancer stem cells (CSCs) exhibiting dual characteristics of cell-cycle activity and immune progenitor features, a finding that clarifies the fundamental mechanism by which these cells evade immune surveillance. In conclusion, we propose that stem cell camouflage constitutes the core mechanism underlying bone marrow hematopoietic dysfunction and drives immune evasion in SACC. These findings highlight the IL17RB-NOTCH1 signaling axis as a promising therapeutic target, offering potential to overcome the long-standing challenges associated with NOTCH1-targeted therapies in this malignancy. SignificanceOur 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 O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=107 SRC="FIGDIR/small/688163v2_ufig1.gif" ALT="Figure 1"> View larger version (36K): org.highwire.dtl.DTLVardef@18c22a2org.highwire.dtl.DTLVardef@135e381org.highwire.dtl.DTLVardef@eb4eadorg.highwire.dtl.DTLVardef@7a51c4_HPS_FORMAT_FIGEXP M_FIG C_FIG Dichotomous gene mapping and single-cell interactome reveal the microenvironmental specificity of NOTCH1/MYB regulation of T/B-cell differentiation and its distinct signaling flows.