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Determinants of anti-PD-1 response and resistance in clear cell renal cell carcinoma

Lewis Au1, Emine Hatipoglu2, Marc Robert de Massy3

  • 1Cancer Dynamics Laboratory, The Francis Crick Institute, London NW1 1AT, UK; Renal and Skin Unit, The Royal Marsden NHS Foundation Trust, London SW3 6JJ, UK.

Cancer Cell
|October 29, 2021
PubMed

Insights

Pre-existing immunity and T cell maintenance, not tumor genomics, predict response to nivolumab (anti-PD-1) in clear cell renal cell carcinoma (ccRCC). This suggests boosting existing T cell responses is key for anti-PD-1 therapy.

Area of Science:

  • Immunology
  • Oncology
  • Genomics

Background:

  • Metastatic clear cell renal cell carcinoma (ccRCC) remains a significant clinical challenge.
  • Understanding the mechanisms of response to immune checkpoint inhibitors like nivolumab (anti-PD-1) is crucial for optimizing treatment strategies.

Purpose of the Study:

  • To investigate the mechanisms underlying clinical response to nivolumab in treatment-naive metastatic ccRCC patients.
  • To explore the correlation between tumor molecular features, T cell receptor (TCR) repertoire, and therapeutic outcomes.

Main Methods:

  • Prospective phase II clinical study (ADAPTeR) involving 15 treatment-naive ccRCC patients.
  • Analysis of 115 multiregion tumor samples.
  • Genomic profiling and T cell receptor (TCR) sequencing.
  • Assessment of nivolumab-bound CD8+ T cells and their functional markers (GZMK/B).

Main Results:

  • No correlation was found between tumor molecular features and clinical response.
  • Expression of ccRCC-specific human endogenous retroviruses indirectly correlated with response.
  • Responders exhibited a higher number of expanded TCR clones pre-treatment, indicating pre-existing immunity.
  • Maintenance of TCR clusters post-treatment predicted response, suggesting sustained antigen recognition.
  • Nivolumab-bound CD8+ T cells in responders were expanded and expressed GZMK/B, with maintenance of clones correlating with response.

Conclusions:

  • Clinical response to nivolumab in ccRCC is not driven by tumor genomics but by pre-existing T cell immunity.
  • The maintenance and boosting of pre-existing T cell responses appear to be a critical mechanism of anti-PD-1 therapy.
  • Future strategies may focus on enhancing or preserving existing anti-tumor T cell activity for improved ccRCC treatment outcomes.
Keywords:
T cell receptorTCR clonal maintenanceTCR clonal replacementanti-PD-1autopsyclear cell renal cell carcinomahuman endogenous retrovirusmultiregionnivolumab

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