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PD-L1 in tumor microenvironment mediates resistance to oncolytic immunotherapy

Dmitriy Zamarin1,2,3,4,5, Jacob M Ricca3,4, Svetlana Sadekova6

  • 1Department of Medicine, Memorial Sloan Kettering Cancer Center (MSKCC), New York, New York, USA.

The Journal of Clinical Investigation
|March 6, 2018
PubMed

Insights

Oncolytic virus (OV) therapy combined with PD-1/PD-L1 blockade shows promise for cancer treatment. This combination overcomes immune resistance, leading to tumor rejection and improved therapeutic outcomes.

Area of Science:

  • Immunology
  • Virology
  • Oncology

Background:

  • Intralesional oncolytic virus (OV) therapy activates immune responses, suggesting potential for combination therapies.
  • Newcastle disease virus (NDV) is an OV used to explore immune targets.
  • Understanding immune resistance mechanisms is crucial for optimizing OV-based cancer treatments.

Purpose of the Study:

  • To identify immune targets upregulated by OV treatment.
  • To investigate the role of programmed death ligand 1 (PD-L1) in OV-mediated immune resistance.
  • To evaluate the efficacy of combining OV therapy with PD-1/PD-L1 blockade.

Main Methods:

  • Utilized human tumor histocultures and syngeneic tumor models.
  • Treated models with Newcastle disease virus (NDV).
  • Administered systemic PD-1 or PD-L1 blockade in combination with intratumoral NDV.

Main Results:

  • NDV treatment induced effector T lymphocyte infiltration but was met with PD-L1-mediated immune inhibition.
  • PD-L1 blockade counteracted adaptive immune resistance to NDV.
  • Combination therapy led to the rejection of both treated and distant tumors.

Conclusions:

  • PD-1/PD-L1 blockade can enhance the efficacy of oncolytic virus therapy.
  • Timing of PD-1/PD-L1 blockade is critical for combination strategies with OVs.
  • Identifying adaptive immune resistance mechanisms informs the rational design of combinatorial OV therapies.
Keywords:
Gene therapyImmunologyImmunotherapyOncologyT cells

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