Prediction of immunotherapy response using mutations to cancer protein assemblies

Sci Adv. 2024 Sep 20;10(38):eado9746. doi: 10.1126/sciadv.ado9746. Epub 2024 Sep 20.

Abstract

While immune checkpoint inhibitors have revolutionized cancer therapy, many patients exhibit poor outcomes. Here, we show immunotherapy responses in bladder and non-small cell lung cancers are effectively predicted by factoring tumor mutation burden (TMB) into burdens on specific protein assemblies. This approach identifies 13 protein assemblies for which the assembly-level mutation burden (AMB) predicts treatment outcomes, which can be combined to powerfully separate responders from nonresponders in multiple cohorts (e.g., 76% versus 37% bladder cancer 1-year survival). These results are corroborated by (i) engineered disruptions in the predictive assemblies, which modulate immunotherapy response in mice, and (ii) histochemistry showing that predicted responders have elevated inflammation. The 13 assemblies have diverse roles in DNA damage checkpoints, oxidative stress, or Janus kinase/signal transducers and activators of transcription signaling and include unexpected genes (e.g., PIK3CG and FOXP1) for which mutation affects treatment response. This study provides a roadmap for using tumor cell biology to factor mutational effects on immune response.

MeSH terms

  • Animals
  • Carcinoma, Non-Small-Cell Lung / drug therapy
  • Carcinoma, Non-Small-Cell Lung / genetics
  • Carcinoma, Non-Small-Cell Lung / immunology
  • Humans
  • Immune Checkpoint Inhibitors / pharmacology
  • Immune Checkpoint Inhibitors / therapeutic use
  • Immunotherapy* / methods
  • Lung Neoplasms / drug therapy
  • Lung Neoplasms / genetics
  • Lung Neoplasms / immunology
  • Lung Neoplasms / pathology
  • Mice
  • Mutation*
  • Neoplasm Proteins / genetics
  • Neoplasm Proteins / immunology
  • Neoplasms / drug therapy
  • Neoplasms / genetics
  • Neoplasms / immunology
  • Neoplasms / therapy
  • Treatment Outcome
  • Urinary Bladder Neoplasms / drug therapy
  • Urinary Bladder Neoplasms / genetics
  • Urinary Bladder Neoplasms / immunology
  • Urinary Bladder Neoplasms / therapy

Substances

  • Neoplasm Proteins
  • Immune Checkpoint Inhibitors