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Response to Programmed Cell Death-1 Blockade in a Murine Melanoma Syngeneic Model Requires Costimulation, CD4, and

Blanca Homet Moreno1, Jesse M Zaretsky2, Angel Garcia-Diaz1

  • 1Division of Hematology/Oncology, Department of Medicine, University of California (UCLA), Los Angeles, California.

Cancer Immunology Research
|September 4, 2016
PubMed

Insights

Programmed cell death protein 1 (PD-1) blockade shows antitumor activity in some cancer models by requiring T cells and costimulation. This therapy

Area of Science:

  • Immunology and Cancer Research
  • Tumor Microenvironment and Immune Response

Background:

  • Programmed cell death protein 1 (PD-1) inhibition improves cancer treatment by modulating T-cell activity.
  • Understanding PD-1 blockade's impact on tumor-host interactions is crucial for optimizing cancer immunotherapy.

Purpose of the Study:

  • To investigate how PD-1 blockade therapy affects tumor-host interactions in syngeneic murine cancer models.
  • To identify factors influencing differential responses to PD-1/PD-L1 blockade in melanoma and colon adenocarcinoma models.

Main Methods:

  • Evaluation of three syngeneic murine tumor models: BRAF-mutant melanomas (YUMM1.1, YUMM2.1) and colon adenocarcinoma (MC38).
  • Assessment of anti-PD-1/anti-PD-L1 therapy efficacy, PD-L1 expression, mutational load, and immune cell infiltration.
  • RNA sequencing analysis to compare inflammatory profiles and gene expression related to immune cell recruitment.

Main Results:

  • Anti-PD-1/PD-L1 therapy demonstrated significant antitumor activity in MC38 and YUMM2.1 models, but not YUMM1.1.
  • PD-L1 expression levels were similar across models, irrespective of interferon stimulation.
  • YUMM2.1 response to PD-1 blockade critically depended on CD4/CD8 T cells, CD28/CD80/86 costimulation, and increased dendritic cells and macrophages.

Conclusions:

  • Response to PD-1 blockade therapy is model-dependent and requires specific immune components.
  • Effective PD-1 blockade necessitates CD4 and CD8 T cells, along with dendritic cell and macrophage-mediated costimulation.
  • YUMM2.1 exhibits a more inflammatory profile, correlating with increased chemokine gene expression and immune cell recruitment.

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