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Neoantigen immunogenicity landscapes and evolution of tumor ecosystems during immunotherapy with nivolumab

Tyler J Alban1,2, Nadeem Riaz3, Prerana Parthasarathy1,2

  • 1Center for Immunotherapy and Precision Immuno-Oncology, Cleveland Clinic, Cleveland, OH, USA.

Nature Medicine
|September 30, 2024
PubMed

Insights

Immune checkpoint blockade with nivolumab in non-small cell lung cancer selects against immunogenic neoantigens, impacting treatment response. Understanding neoantigen features improves therapy efficacy.

Area of Science:

  • Oncology
  • Immunology
  • Cancer Genomics

Background:

  • Immune checkpoint blockade (ICB) efficacy is driven by neoantigen immunoediting, but neoantigen characteristics and their role in treatment response are not fully understood.
  • Nivolumab is an immune checkpoint inhibitor used in cancer therapy, particularly for non-small cell lung cancer (NSCLC).
  • Neoantigens are tumor-specific antigens that can elicit an immune response, making them crucial targets for cancer immunotherapy.

Purpose of the Study:

  • To investigate the molecular features of neoantigens and their immunogenicity in non-small cell lung cancer patients treated with nivolumab.
  • To understand how neoantigen immunoediting influences the efficacy of immune checkpoint blockade.
  • To identify specific features of neoantigens that correlate with T cell recognition and clinical response.

Main Methods:

  • Analysis of biopsy samples from 80 non-small cell lung cancer patients in the CheckMate 153 trial before and during nivolumab treatment.
  • Examination of 1,453 candidate neoantigens, assessing their cancer cell fraction and T cell recognition.
  • Mapping neoantigens to clonal dynamics, evolutionary trajectories, and clinical response data.

Main Results:

  • Early loss of mutations and neoantigens during nivolumab therapy correlated with clinical benefit.
  • 196 neopeptides recognized by T cells were identified, with a strong selection against immunogenic neoantigen-harboring clones.
  • Position-specific amino acid and physiochemical features associated with immunogenicity were identified, leading to the development of an immunogenicity score.
  • Nivolumab-induced tumor microenvironment evolution in NSCLC showed similarities and differences compared to melanoma.

Conclusions:

  • Neoantigen immunoediting plays a critical role in the efficacy of nivolumab in non-small cell lung cancer.
  • The study provides detailed molecular insights into neoantigen landscapes and their evolution during ICB.
  • Identifying immunogenic neoantigen features can inform the development of more effective cancer immunotherapies.

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