ASCL2 induces an immune excluded microenvironment by activating cancer-associated fibroblasts in microsatellite stable colorectal cancer

  • Oncogene. 2023 Aug 17. doi: 10.1038/s41388-023-02806-3.
Dan Zhang  #  1  2 ,  Qi-Qi Ni  #  1  2 ,  Qiao-Yan Liang  1  2 ,  Li-Ling He  1  2 ,  Bo-Wen Qiu  1  2 ,  Ling-Jie Zhang  1  2 ,  Ting-Yu Mou  3 ,  Chen-Chen Le  1  2 ,  Yuan Huang  1  2 ,  Ting-Ting Li  1  2 ,  Shu-Yang Wang  1  2 ,  Yan-Qing Ding  4  5 ,  Hong-Li Jiao  6  7 ,  Ya-Ping Ye  8  9
Affiliations
  • 1. Department of Pathology, School of Basic Medical Sciences and Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China.
  • 2. Guangdong Province Key Laboratory of Molecular Tumor Pathology, Guangzhou, Guangdong, China.
  • 3. Department of General Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China.
  • 4. Department of Pathology, School of Basic Medical Sciences and Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China. [email protected].
  • 5. Guangdong Province Key Laboratory of Molecular Tumor Pathology, Guangzhou, Guangdong, China. [email protected].
  • 6. Department of Pathology, School of Basic Medical Sciences and Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China. [email protected].
  • 7. Guangdong Province Key Laboratory of Molecular Tumor Pathology, Guangzhou, Guangdong, China. [email protected].
  • 8. Department of Pathology, School of Basic Medical Sciences and Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China. [email protected].
  • 9. Guangdong Province Key Laboratory of Molecular Tumor Pathology, Guangzhou, Guangdong, China. [email protected].
  • # Contributed equally.
PMID: 37591954 DOI: 10.1038/s41388-023-02806-3
Abstract

Proficient mismatch repair or microsatellite stable (pMMR/MSS) colorectal cancers (CRCs) are vastly outnumbered by deficient mismatch repair or microsatellite instability-high (dMMR/MSI-H) tumors and lack a response to immune checkpoint inhibitors (ICIs). In this study, we reported two distinct expression patterns of ASCL2 in pMMR/MSS and dMMR/MSI-H CRCs. ASCL2 is overexpressed in pMMR/MSS CRCs and maintains a stemness phenotype, accompanied by a lower density of tumor-infiltrating lymphocytes (TILs) than those in dMMR/MSI CRCs. In addition, coadministration of anti-PD-L1 antibodies facilitated T cell infiltration and provoked strong antitumor immunity and tumor regression in the MC38/shASCL2 mouse CRC model. Furthermore, overexpression of ASCL2 was associated with increased TGFB levels, which stimulate local Cancer-associated fibroblasts (CAFs) activation, inducing an immune-excluded microenvironment. Consistently, mice with deletion of Ascl2 specifically in the intestine (Villin-Cre+, Ascl2 flox/flox, named Ascl2 CKO) revealed fewer activated CAFs and higher proportions of infiltrating CD8+ T cells; We further intercrossed Ascl2 CKO with APCMin/+ model suggesting that Ascl2-deficient expression in intestinal represented an immune infiltrating environment associated with a good prognosis. Together, our findings indicated ASCL2 induces an immune excluded microenvironment by activating CAFs through transcriptionally activating TGFB, and targeting ASCL2 combined with ICIs could present a therapeutic opportunity for MSS CRCs.

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