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

  1. Guoliang Yang
  2. Xudong Wang
  3. Tian Ye
  4. Tingyao Ma
  5. Youmei Chen
  6. Fang Nan
  7. Qian Chen
  8. Lu Kong
  9. Xiaohong Chen
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Abstract

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.

<fig id="ufig1" position="float" orientation="portrait" fig-type="figure"> <label>Graphical Abstract</label> <caption>

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.

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