Gastroesophageal adenocarcinoma (GEA) treatment has been revolutionized by the introduction of immune checkpoint inhibitors (CPIs) that, in combination with platinum-based chemotherapy as first line, have improved both progression-free survival (PFS) and overall survival (OS). However, there is an urgent need for the identification of predictive biomarkers of response, particularly for patients with a combined positive score (CPS)<5, where the benefit deriving form CPIs is less clear. We propose a novel immune classification for advanced GEA which in combination with CPS could improve patient selection for precision immunotherapy.
31 paraffin-embedded GEA tumor samples available for molecular analyses from metastatic, CPS<5 and chemotherapy naïve patients were collected from January 2004 to January 2019. A transcriptomic analysis using nCounter PanCancer Immune Profiling panel (Nanostring) was performed to study tumor microenvironment features. To validate the results, 23 fresh GEA biopsies were prospectively collected from January 2020 to September 2021 and characterized with RNA-seq analysis.
Both Nanostring® and RNA-seq transcriptomic data were studied. We analyzed the cell types composing the immune infiltrate and their functional activity. This integrative study allowed the identification of four different groups across our patients. Among them, we identified a subgroup of patients whose tumors presented an enriched immune infiltrate (including dendritic cells, B cells, CD8+ T cells and macrophages) showing high immune function activity. Interestingly, these tumors expressed the most gene signatures related to immunomodulatory pathways –composed of genes such as PD-L1, PD-1, CTLA-4, TIGIT and LAG3– and immunotherapy response, highlighting they could potentially achieve the best benefit from CPIs, despite presenting CPS<5.
Our work allows the identification of an immune-enriched subtype of advanced GEA, characterized by high immune cell activity, which could potentially help achieve a more precise immunotherapy approach. Further validations are awaited.
The authors.
This work was supported by grants from the Carlos III Health Institute [grant number PI18/01508 and PI21/0693] to TF, [grant number PI18/01909 and PI21/00689] to AC and NT and [grant number PI21/00695] to CM. MCS was supported with a predoctoral grant by the Spanish Association against Cancer (AECC, Valencia-2019). VG was funded by a Joan Rodés contract JR21/00042 from the Carlos III Health Institute; FGV was founded by a post doc grant by Generalitat Valenciana Grant APOSTD/2021/168; NT was funded by Joan Rodés contract JR20/00005 from the Carlos III Health Institute. DR was funded by Joan Rodés contract JR16/00040 from the Carlos III Health Institute. JC was granted with a VLC Bioclinic grant 2021/257 from the University of Valencia. SZT was granted by a grant CA18/00042 contract for bioinformaticians from Carlos III. TF was supported by Joan Rodés contract JR17/00026 from the Carlos III Health Institute.
A. Cervantes: Financial Interests, Institutional, Advisory Board: Merck Serono, Amgen, Roche, Transgene, AnHeart Therapeutics; Financial Interests, Institutional, Invited Speaker: Amgen, Roche, Merck Serono, Foundation Medicine; Financial Interests, Personal, Other, Associate Editor: Annals of Oncology, ESMO Open; Financial Interests, Personal, Other, Editor: Cancer Treatment Reviews; Financial Interests, Institutional, Research Grant, Principal Investigator: Actuate Therapeutic, Amgen, Astellas Pharma, Beigene, Bayer, AstraZeneca, BMS, Amcure, FibroGen, Lilly, Genentech, MedImmune, Merck Serono, Novartis, Natera, MSD, Servier, Sierra Oncology, Adaptimmune, Takeda; Non-Financial Interests, Personal, Other, General and Scientific Director: INCLIVA Biomedical Research Institute. All other authors have declared no conflicts of interest.