The immune microenvironment of HPV-negative oral squamous cell carcinoma from never-smokers and never-drinkers patients suggests higher clinical benefit of IDO1 and PD1/PD-L1 blockade

Jean‐philippe Foy (1, 2, 3) , Chloé Bertolus (2, 4) , Marie-Cécile Michallet (1) , Sophie Deneuve (1, 3) , R. Incitti (5) , Nathalie Bendriss-Vermare (1) , Marie Alexandra Albaret (1, 5) , Sandra Ortiz-Cuaran (1, 5) , Emilie Thomas (5) , A. Colombe (1, 3) , C. Py (1, 3) , Nicolas Gadot (1, 3) , Jean-Philippe Michot (1, 3, 5) , Jerôme Fayette (1, 3) , Alain Viari (6, 7, 5) , Benoit van den Eynde (8) , Patrick Goudot (2, 4) , Mojgan Devouassoux-Shisheboran (9) , Alain Puisieux (1) , Christophe Caux (1) , Philippe Zrounba (1, 3) , Sylvie Lantuejoul (1, 3) , Pierre Saintigny (1, 3)

1 UNICANCER/CRCL - Centre de Recherche en Cancérologie de Lyon
2 CHU Pitié-Salpêtrière [AP-HP]
3 Centre Léon Bérard [Lyon]
4 GPTM - Génétique et Physiopathologie des Tissus Musculaires
5 Synergie Lyon Cancer-Platform of Bioinformatics-Gilles Thomas
6 Baobab [LBBE]
7 ERABLE - Equipe de recherche européenne en algorithmique et biologie formelle et expérimentale
8 UCL - Université Catholique de Louvain = Catholic University of Louvain
9 Hôpital de la Croix-Rousse [CHU - HCL]

Never-smokers and never-drinkers patients (NSND) suffering from oral squamous cell carcinoma (OSCC) are epidemiologically different from smokers drinkers (SD). We therefore hypothesized that they harbored distinct targetable molecular alterations.PATIENTS AND METHODS:Data from The Cancer Genome Atlas (TCGA) (discovery set), Gene Expression Omnibus and Centre Léon Bérard (CLB) (3 validation sets) with available gene expression profiles of HPV-negative OSCC from NSND and SD were mined. Protein expression profiles and genomic alterations were also analyzed from TCGA, and a functional pathway enrichment analysis was performed. Formalin-fixed paraffin-embedded (FFPE) samples from 44 OSCC including 20 NSND and 24 SD treated at CLB were retrospectively collected to perform targeted-sequencing of 2,559 transcripts (HTG EdgeSeq system), and CD3, CD4, CD8, IDO1 and PD-L1 expression analyses by immunohistochemistry (IHC). Enrichment of a six-gene interferon-γ signature of clinical response to pembrozulimab (PD-1 inhibitor) was evaluated in each sample from all cohorts, using the single sample gene set enrichment analysis method. : A total of 854 genes and 29 proteins were found to be differentially expressed between NSND and SD in TCGA. Functional pathway analysis highlighted an overall enrichment for immune-related pathways in OSCC from NSND, especially involving T-cell activation. Interferon-γ response and PD1 signaling were strongly enriched in NSND. IDO1 and PD-L1 were overexpressed and the score of response to pembrolizumab was higher in NSND compared to SD, although the mutational load was lower in NSND. IHC analyses in the CLB cohort evidenced IDO1 and PD-L1 overexpression in tumor cells that was associated with a higher rate of tumor-infiltrating T-cells in NSND compared to SD. The main biological and actionable difference between OSCC from NSND and SD lies in the immune microenvironment, suggesting a higher clinical benefit of PD-L1 and IDO1 inhibition in OSCC from NSND.

Domaines: Cancer

Jean‐philippe Foy, Chloé Bertolus, Marie-Cécile Michallet, Sophie Deneuve, R. Incitti, et al.. The immune microenvironment of HPV-negative oral squamous cell carcinoma from never-smokers and never-drinkers patients suggests higher clinical benefit of IDO1 and PD1/PD-L1 blockade. Annals of Oncology, 2017, 28 (8), pp.1934-1941. ⟨10.1093/annonc/mdx210⟩. ⟨hal-01560943⟩