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The Challenges of Tumor Mutational Burden as an Immunotherapy Biomarker

Denis L Jardim1, Aaron Goodman2, Debora de Melo Gagliato3

  • 1Centro de Oncologia Hospital Sírio Libanês-São Paulo, São Paulo, Brazil.

Cancer Cell
|October 30, 2020
PubMed

Insights

Tumor mutational burden (TMB) indicates cancer mutation levels and can predict responses to immune checkpoint inhibitors (ICIs). However, TMB alone is insufficient, necessitating composite biomarkers for better patient stratification.

Area of Science:

  • Oncology
  • Immunology
  • Genetics

Background:

  • Tumor mutational burden (TMB) quantifies cancer mutations, which can be processed into neo-antigens.
  • Neo-antigens presented by major histocompatibility complex (MHC) proteins engage T cells.
  • Cancer immune evasion occurs via checkpoints that suppress T cell activity.

Purpose of the Study:

  • To evaluate the predictive value of TMB for immune checkpoint inhibitor (ICI) therapy outcomes.
  • To identify the limitations of TMB as a sole biomarker for ICI response.
  • To advocate for the development of composite biomarkers.

Main Methods:

  • Analysis of TMB in relation to neo-antigen formation and T cell recognition.
  • Correlation of TMB levels with clinical outcomes in patients treated with ICIs.
  • Review of mechanisms of cancer immune evasion and T cell regulation.

Main Results:

  • Higher TMB generally correlates with increased neo-antigens and improved ICI outcomes.
  • TMB is an imperfect predictor, as many patients do not benefit from ICIs.
  • Existing biomarkers do not fully capture the complexity of anti-tumor immunity.

Conclusions:

  • While TMB is a valuable biomarker, it is insufficient for predicting ICI response.
  • A composite biomarker incorporating TMB, MHC, and T cell receptor repertoire is needed.
  • Improved biomarkers are crucial for patient selection and optimizing cancer immunotherapy.
Keywords:
biomarkercancer therapygeneticsimmunotherapymutattional load

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