Association between PD1 mRNA and response to anti-PD1 monotherapy across multiple cancer types

L. Paré, T. Pascual, E. Seguí, C. Teixidó, M. Gonzalez-Cao, P. Galván, A. Rodríguez, B. González, M. Cuatrecasas, E. Pineda, A. Torné, G. Crespo, S. Martin-Algarra, E. Pérez-Ruiz, Reig, M. Viladot, C. Font, B. Adamo, M. Vidal, L. GabaM. Muñoz, I. Victoria, G. Ruiz, N. Viñolas, B. Mellado, J. Maurel, J. Garcia-Corbacho, M. Molina-Vila, M. Juan, J. M. Llovet, N. Reguart, A. Arance, A. Prat

Research output: Contribution to journalArticlepeer-review

81 Scopus citations

Abstract

Background: We hypothesized that the abundance of PD1 mRNA in tumor samples might explain the differences in overall response rates (ORR) observed following anti-PD1 monotherapy across cancer types. Patients and methods: RNASeqv2 data from 10 078 tumor samples representing 34 different cancer types was analyzed from TCGA. Eighteen immune-related gene signatures and 547 immune-related genes, including PD1, were explored. Correlations between each gene/signature and ORRs reported in the literature following anti-PD1 monotherapy were calculated. To translate the in silico findings to the clinical setting, we analyzed the expression of PD1 mRNA using the nCounter platform in 773 formalin-fixed paraffin embedded (FFPE) tumor samples across 17 cancer types. To test the direct relationship between PD1 mRNA, PDL1 immunohistochemistry (IHC), stromal tumor-infiltrating lymphocytes (sTILs) and ORR, we evaluated an independent FFPE-based dataset of 117 patients with advanced disease treated with anti-PD1 monotherapy. Results: In pan-cancer TCGA, PD1 mRNA expression was found strongly correlated (r > 0.80) with CD8 T-cell genes and signatures and the proportion of PD1 mRNA-high tumors (80th percentile) within a given cancer type was variable (0%-84%). Strikingly, the PD1-high proportions across cancer types were found strongly correlated (r ¼ 0.91) with the ORR following anti-PD1 monotherapy reported in the literature. Lower correlations were found with other immune-related genes/signatures, including PDL1. Using the same population-based cutoff (80th percentile), similar proportions of PD1-high disease in a given cancer type were identified in our in-house 773 tumor dataset as compared with TCGA. Finally, the pre-established PD1 mRNA FFPE-based cutoff was found significantly associated with anti-PD1 response in 117 patients with advanced disease (PD1-high 51.5%, PD1-intermediate 26.6% and PD1-low 15.0%; odds ratio between PD1-high and PD1-intermediate/low ¼ 8.31; P < 0.001). In this same dataset, PDL1 tumor expression by IHC or percentage of sTILs was not found associated with response. Conclusions: Our study provides a clinically applicable assay that links PD1 mRNA abundance, activated CD8 T-cells and anti-PD1 efficacy.

Original languageEnglish
Pages (from-to)2121-2128
Number of pages8
JournalAnnals of Oncology
Volume29
Issue number10
DOIs
StatePublished - Oct 2018
Externally publishedYes

Keywords

  • Anti-PD1
  • Gene expression
  • Immunotherapy
  • PD1
  • Solid tumors

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