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Adoptive T Cell Therapy Targeting Different Gene Products Reveals Diverse and Context-Dependent Immune Evasion in

Maike Effern1, Nicole Glodde2, Matthias Braun3

  • 1Institute of Experimental Oncology (IEO), Medical Faculty, University Hospital Bonn, University of Bonn, Bonn 53105, Germany; Department of Microbiology & Immunology, The University of Melbourne at the Peter Doherty Institute for Infection & Immunity, Melbourne, VIC, Australia.

Immunity
|August 5, 2020
PubMed

Insights

Choosing the right cancer target antigen is crucial for effective T cell therapy. Different targets lead to distinct tumor escape mechanisms, impacting treatment success and guiding future immunotherapy design.

Area of Science:

  • Immunology
  • Oncology
  • Genetics

Background:

  • Tumor immune escape hinders durable responses to T cell therapy.
  • Understanding how target antigen regulation affects therapeutic efficacy is critical.

Purpose of the Study:

  • To investigate how gene products as T cell targets influence anti-tumor immunity and therapeutic resistance.
  • To explore diverse immune escape mechanisms in melanoma models.

Main Methods:

  • Utilized a CRISPR-Cas9 method (CRISPitope) to fuse a CD8+ T cell epitope to various endogenous gene products in melanoma models.
  • Employed adoptive cell transfer (ACT) targeting melanosomal proteins versus oncogenic CDK4R24C.

Main Results:

  • Targeting melanosomal proteins, unlike CDK4R24C, induced melanoma dedifferentiation and increased myeloid cell infiltration.
  • CDK4R24C antigen persistence created an interferon-high, T cell-rich tumor microenvironment.
  • Immune checkpoint inhibition served as effective salvage therapy for CDK4R24C-targeted tumors.

Conclusions:

  • The selection of target antigen dictates the phenotype and immune landscape of recurrent melanomas.
  • Findings have significant implications for designing more effective cancer immunotherapies.
Keywords:
PD-L1adoptive T cell therapyantigen lossdedifferentiationepitopeimmune escapemelanomaphenotype switchingplasticityresistance

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