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Dual CTLA-4 and PD-L1 Blockade Inhibits Tumor Growth and Liver Metastasis in a Highly Aggressive Orthotopic Mouse

E Fiegle1, D Doleschel2, S Koletnik1

  • 1Institute for Experimental Molecular Imaging, Medical Faculty, RWTH Aachen University, Germany.

Neoplasia (New York, N.Y.)
|August 15, 2019
PubMed

Insights

Dual immune checkpoint blockade targeting CTLA-4 and PD-L1 significantly inhibited colon cancer growth and liver metastasis in mice. This approach enhanced anti-tumor T cells and M1 macrophages, demonstrating a promising strategy for aggressive colorectal cancers.

Area of Science:

  • Immunology
  • Oncology
  • Cancer Research

Background:

  • Immune checkpoint inhibitors (ICIs) offer clinical benefits in specific cancers like metastatic microsatellite instable colorectal carcinoma.
  • The full potential and limitations of ICIs in the majority of metastatic colorectal carcinomas remain incompletely understood.
  • Investigating novel therapeutic strategies is crucial for aggressive colon cancer subtypes.

Purpose of the Study:

  • To evaluate the efficacy of sole and dual blockade of cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and programmed death-ligand 1 (PD-L1) in a mouse model of colon cancer.
  • To elucidate the underlying mechanisms of immune response modulation and tumor microenvironment changes induced by these inhibitors.

Main Methods:

  • Utilized a microsatellite stable, highly aggressive orthotopic mouse model of colon cancer.
  • Administered sole and dual blockade of CTLA-4 and PD-L1.
  • Assessed tumor growth, liver metastasis, immune cell infiltration (CD8+, CD4+, Treg), cytokine expression (IFN-γ, IL-1α, IL-2, IL-12, IL-4), macrophage polarization (iNOS+, PD-L1+, Tie2+), and tumor microenvironment characteristics (vascularization, fibroblasts, collagen I) via DCE-MRI and immunohistology.

Main Results:

  • Dual CTLA-4 and PD-L1 blockade led to tumor growth stagnation and complete blockade of liver metastasis.
  • Sole CTLA-4 inhibition was more effective than PD-L1 inhibition alone in reducing metastatic spread.
  • Combined blockade significantly increased intratumoral CD8+ and CD4+ T cells, reduced regulatory T cells (Tregs), promoted M1 macrophage polarization, and increased fibroblast activation and collagen deposition, without altering tumor vascularization.

Conclusions:

  • Dual CTLA-4 and PD-L1 blockade demonstrates synergistic anti-tumor effects in aggressive colon cancer.
  • The efficacy is attributed to enhanced anti-tumorigenic T cell responses and M1 macrophage polarization, alongside increased fibroblast activation.
  • This study highlights a promising combination immunotherapy strategy for microsatellite-stable colorectal cancer.

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