In:
Oncogene, Springer Science and Business Media LLC, Vol. 42, No. 38 ( 2023-09-15), p. 2841-2853
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/sh ASCL2 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 Apc Min/+ 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.
Type of Medium:
Online Resource
ISSN:
0950-9232
,
1476-5594
DOI:
10.1038/s41388-023-02806-3
Language:
English
Publisher:
Springer Science and Business Media LLC
Publication Date:
2023
detail.hit.zdb_id:
2008404-3
