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Area of Science:

  • Immunology
  • Cancer Biology
  • Pharmacology

Background:

  • Exhausted CD8+ T-cells (TEX) exacerbate cancer stem cell (CSC) virulence, posing a therapeutic challenge.
  • Neem Leaf Glycoprotein (NLGP), a plant-derived immunomodulator, has shown immune-dependent tumor restriction.
  • The potential of NLGP to reprogram TEX for targeting CSCs requires investigation.

Purpose of the Study:

  • To investigate the efficacy of NLGP immunotherapy in targeting TEX-induced CSCs.
  • To elucidate the mechanisms by which NLGP affects CSCs and TEX.
  • To evaluate the therapeutic potential of NLGP in combination with chemotherapy.

Main Methods:

  • In vivo B16-F10 melanoma model and in vitro TEX/CSC coculture systems were used.
  • NLGP treatment effects on CSC clonogenicity, drug resistance, and key markers (PDL1, OCT4, SOX2) were assessed.
  • Cell cycle analysis, Western blotting, and Dectin-1, Notch1, and mTOR pathway investigations were performed.

Main Results:

  • NLGP administration significantly reduced CSC virulence in vivo and in vitro.
  • NLGP downregulated CSC clonogenicity, multidrug resistance, PDL1, OCT4, and SOX2.
  • NLGP-educated TEX induced CSCs into the S-phase, enhancing sensitivity to 5-fluorouracil (5FU) and showing nephron protection.

Conclusions:

  • NLGP immunotherapy effectively alleviates TEX-induced CSC aggravation.
  • NLGP reprograms CSCs, increasing their susceptibility to chemotherapy and mitigating 5FU toxicity.
  • Dectin-1-mediated NLGP action highlights a novel immunotherapeutic target for T-cell exhaustion.