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Subclone from CT26 resistant to anti-PD-1 therapy associated with increased expression of genes related to

Yangyang Zhang1, Chaoji Zhang2, Guangyu Chen3

  • 1Department of Surgery, The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, 127 Dongming Road, Jinshui District, Zhengzhou, Henan Province, China.

Translational Oncology
|June 11, 2024
PubMed
Abstract

Insights

Most cancer patients resist anti-PD-1 therapy. Glucocorticoid pathway activation in tumors is linked to this resistance, suggesting new therapeutic targets for improving anti-PD-1 treatment efficacy.

Area of Science:

  • Immunology
  • Oncology
  • Molecular Biology

Background:

  • Anti-PD-1 antibodies revolutionized cancer treatment but face widespread patient resistance.
  • The role of endogenous glucocorticoids (GCs) in this resistance is not well understood.

Purpose of the Study:

  • To investigate the role of endogenous glucocorticoids (GCs) in resistance to anti-PD-1 antibody therapy in colorectal cancer.
  • To identify molecular mechanisms underlying treatment resistance.

Main Methods:

  • Generated single cell-derived cell lines (SCDCLs) from a colorectal cancer cell line (CT26).
  • Analyzed tumor tissues from anti-PD-1 treated and untreated mice using transcriptome sequencing and flow cytometry.
  • Assessed pathway activity and immune cell composition in the tumor microenvironment.

Main Results:

  • One clone (SCC2) showed slower tumor growth but higher T cell infiltration and PD-1 expression, yet no response to anti-PD-1 therapy.
  • Transcriptome analysis revealed increased expression of GC-related genes in the resistant SCC2 tumors.
  • GC pathway activation was observed in tumors resistant to anti-PD-1 therapy.

Conclusions:

  • Glucocorticoid pathway activation is associated with resistance to anti-PD-1 therapy.
  • Targeting the GC pathway may overcome resistance and improve anti-PD-1 treatment outcomes.
Keywords:
Colorectal cancerGlucocorticoidsResistance to anti-PD-1 therapy

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