Early immune remodeling steers clinical response to frontline chemoimmunotherapy in advanced gastric cancer
Menée à partir d'échantillons biopsiques prélevés sur 47 patients atteints d'un adénocarcinome oeso-gastrique de stade avancé et inclus dans un essai clinique de phase II évaluant l'ajout du pembrolizumab à un traitement de première ligne par 5-fluorouracile ou sels de platine, cette étude met en évidence une association entre le remodelage immunitaire précoce du microenvironnement tumoral et la réponse clinique
Adding anti-PD1 to 5-FU/platinum improves survival in some advanced gastroesophageal adenocarcinomas (GEA). To understand the effects of chemotherapy and immunotherapy we conducted a phase II frontline trial (n = 47) sequentially adding pembrolizumab to 5-FU/platinum in advanced GEA. Using serial biopsy of the primary tumor at baseline, after one cycle of 5-FU/platinum, and after the addition of pembrolizumab we transcriptionally profiled 358,067 single cells to identify evolving multicellular TME networks. Chemotherapy induced early on-treatment multicellular hubs with tumor-reactive T-cell and M1-like macrophage interactions in slow progressors. Faster progression featured increased MUC5A and MSLN containing treatment-resistance programs in tumor cells and M2-like macrophages with immunosuppressive stromal interactions. After pembrolizumab we observed increased CD8 T-cell infiltration and development of an immunity hub involving tumor-reactive CXCL13 T-cell program and epithelial interferon-stimulated gene programs. Strategies to drive increases in anti-tumor immune hub formation could expand the portion of patients benefiting from anti-PD1 approaches.
Cancer Discovery , article en libre accès, 2023