Subclone from CT26 Resistant to Anti-PD-1 Therapy Associated with Increased Expression of Genes Related to Glucocorticoids

Overview

Journal Transl Oncol

Specialty Oncology

Date 2024 Jun 11

PMID 38861853

Authors

Yangyang Zhang

Chaoji Zhang

Guangyu Chen

Hongqin You

Sen Wang

Xiaoming Wang

Peng Zhao

Benling Xu

Quanli Gao

Long Yuan

Affiliations

Soon will be listed here.

Abstract

Background: Although the use of anti-PD-1 antibodies has fundamentally changed traditional cancer treatment, most patients are resistant to anti-PD-1 treatment. Glucocorticoids (GCs) play an important role in tumorigenesis and tumor progression, but the role of endogenous GCs in resistance to anti-PD-1 antibody therapy remains unclear.

Methods: Single cell-derived cell lines (SCDCLs) were generated from a colorectal cancer cell line (CT26) using limiting dilution. We analyzed tumor tissues from anti-PD-1 antibody-treated and untreated mice inoculated with SCDCLs via transcriptome sequencing and flow cytometry to detect pathway activity and immune cell composition changes in the tumor microenvironment.

Results: Five SCDCLs were inoculated into wild-type BALB/c mice (all tumorigenic). Single-cell clone (SCC)-2 exhibited the slowest growth rates both in vivo and in vitro compared to other single-cell clones, and better long-term survival than SCC1 and CT26. Flow cytometry showed that SCC2 tumor-bearing mice exhibited significantly higher infiltration of T cells within the tumor tissue, and higher expression of PD-1 on these T cells than the other groups in vivo. However, the SCC2 group showed no response to anti-PD-1 therapy. Transcriptome analysis revealed that the SCC2 group exhibited increased expression of genes related to GC (Hsd11b1, Sgk3, Tgfbr2, and Il7r) compared to SCC2-anti-PD-1 treated tumors.

Conclusions: GC pathway activation is related to resistance to anti-PD-1 therapy.

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