| First Author | Zhang D | Year | 2023 |
| Journal | Oncogene | Volume | 42 |
| Issue | 38 | Pages | 2841-2853 |
| PubMed ID | 37591954 | Mgi Jnum | J:341097 |
| Mgi Id | MGI:7531906 | Doi | 10.1038/s41388-023-02806-3 |
| Citation | Zhang D, et al. (2023) ASCL2 induces an immune excluded microenvironment by activating cancer-associated fibroblasts in microsatellite stable colorectal cancer. Oncogene 42(38):2841-2853 |
| abstractText | 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 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. |
