2. Academic Validation
  3. ASCL2 induces an immune excluded microenvironment by activating cancer-associated fibroblasts in microsatellite stable colorectal cancer

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

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. dyqsmu@126.com.
  • 5 Guangdong Province Key Laboratory of Molecular Tumor Pathology, Guangzhou, Guangdong, China. dyqsmu@126.com.
  • 6 Department of Pathology, School of Basic Medical Sciences and Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China. 25048195@qq.com.
  • 7 Guangdong Province Key Laboratory of Molecular Tumor Pathology, Guangzhou, Guangdong, China. 25048195@qq.com.
  • 8 Department of Pathology, School of Basic Medical Sciences and Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China. yeyp1980@126.com.
  • 9 Guangdong Province Key Laboratory of Molecular Tumor Pathology, Guangzhou, Guangdong, China. yeyp1980@126.com.
  • # 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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