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Clinical and molecular features of acquired resistance to immunotherapy in non-small cell lung cancer

Danish Memon1, Adam J Schoenfeld2, Darwin Ye3

  • 1European Molecular Biology Laboratory (EMBL), European Bioinformatics Institute, Wellcome Genome Campus, Hinxton, Cambridge, UK; Cancer Research UK Cambridge Institute, University of Cambridge, Li Ka Shing Centre, Robinson Way, Cambridge, UK; M:M Bio Limited, 99 Park Drive, Milton, Abingdon, UK.

Cancer Cell
|January 12, 2024
PubMed

Insights

Acquired resistance to PD-(L)1 blockade immunotherapy is common in non-small cell lung cancer (NSCLC). Relapsed tumors show altered inflammation and interferon signaling, offering targets for new therapies.

Area of Science:

  • Oncology
  • Immunology
  • Cancer Research

Background:

  • Immunotherapy with PD-(L)1 blockade is a standard treatment for non-small cell lung cancer (NSCLC).
  • Mechanisms of acquired resistance to PD-(L)1 blockade in NSCLC are not well understood.
  • Over 60% of initial responders develop acquired resistance.

Purpose of the Study:

  • To investigate the molecular characteristics of acquired resistance to PD-(L)1 blockade in NSCLC.
  • To identify potential therapeutic strategies to overcome acquired resistance.

Main Methods:

  • Analysis of tumor samples from 1,201 NSCLC patients treated with PD-(L)1 blockade.
  • Differential gene expression analysis focusing on inflammation and interferon signaling pathways.
  • Validation in murine models of acquired resistance.

Main Results:

  • Acquired resistance is associated with differential expression of inflammation and interferon (IFN) signaling.
  • Relapsed tumors exhibit either upregulated or stable expression of IFNγ response genes.
  • Upregulation of IFNγ response genes correlates with immune dysfunction and mutations in antigen presentation genes.
  • Murine models recapitulated key features of acquired resistance after IFNγ treatment.

Conclusions:

  • Acquired resistance to PD-(L)1 blockade in NSCLC involves an ongoing, altered IFN response.
  • The tumor microenvironment in acquired resistance remains inflamed, suggesting potential for therapeutic reprogramming.
  • Understanding these altered immune responses can guide strategies to reverse acquired resistance.
Keywords:
Clonal selectionGenomics and TranscriptomicsImmune escapeImmune-checkpoint blockadeInterferon alpha/gamma responseNeoantigensT cell exhaustionTumor heterogeneityType I and Type II Interferonsanti-PD-1 therapy

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