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Pré-Publication, Document De Travail Année : 2023

Microenvironment of metastatic site reveals key predictors of PD-1 blockade response in renal cell carcinoma

Florian Jeanneret
Sarah Schoch
  • Fonction : Auteur
In Hwa Um
  • Fonction : Auteur
Assilah Bouzit
  • Fonction : Auteur
Bertrand Evrard
  • Fonction : Auteur
Evan Seffar
  • Fonction : Auteur
Frédéric Chalmel
Javier Alfaro
  • Fonction : Auteur
Catia Pesquita
  • Fonction : Auteur
Fabio Massimo Zanzotto
  • Fonction : Auteur
Mark Stares
  • Fonction : Auteur
Stefan Symeonides
  • Fonction : Auteur
Alexander Laird
  • Fonction : Auteur
Jean-Alexandre Long
  • Fonction : Auteur
Jean Luc Descotes
  • Fonction : Auteur
Delphine Pflieger
  • Fonction : Auteur
David Harrison
  • Fonction : Auteur
Odile Filhol
Håkan Axelson
  • Fonction : Auteur
Christophe Battail

Résumé

ABSTRACT Immune checkpoint blockade (ICB) therapies have globally improved the overall survival (OS) of patients with advanced cancers. However, the response rate to these treatments vary widely among patients, therefore exposing non-responders to immune-related adverse events, causing an urgent need of prior-treatment predictors of response to ICB. We investigated the tumor microenvironment (TME) of clear cell renal cell carcinoma (ccRCC) samples from primary and metastatic sites to identify predictive molecular and cellular markers of response to ICB. We revealed a significant discrepancy in treatment response between TME subgroups inferred from metastatic sites. The C3 cluster was enriched in non-responders and harbored a lower fractions of T-CD8 and plasma B cells, as well as a decreased expression of immunoglobulin genes. In addition we developed a highly predictive score that reflects the Tumor-Immunity Differential (TID) in TME to predict immunotherapy response (AUC=0.88, log-rank tests for PFS P < 0.0001, OS P = 0.01). In addition, among TID-related genes (YWHAE, CXCR6 and BTF3), YWHAE was validated as a robust predictive marker of immunotherapy response in independent cohorts of melanoma and lung cancers based on pre or on-treatment biopsies. These findings provide insights into efficient ICB treatment selection in clinical practice for patients with advanced cancers.

Dates et versions

hal-04279022 , version 1 (10-11-2023)

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Florian Jeanneret, Pauline Bazelle, Sarah Schoch, Catherine Pillet, In Hwa Um, et al.. Microenvironment of metastatic site reveals key predictors of PD-1 blockade response in renal cell carcinoma. 2023. ⟨hal-04279022⟩
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