Early Immune Remodeling Steers Clinical Response to First-Line Chemoimmunotherapy in Advanced Gastric Cancer.
Cancer Discov
; 14(5): 766-785, 2024 May 01.
Article
en En
| MEDLINE
| ID: mdl-38319303
ABSTRACT
Adding anti-programmed cell death protein 1 (anti-PD-1) to 5-fluorouracil (5-FU)/platinum improves survival in some advanced gastroesophageal adenocarcinomas (GEA). To understand the effects of chemotherapy and immunotherapy, we conducted a phase II first-line 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 tumor microenvironment (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 antitumor immune hub formation could expand the portion of patients benefiting from anti-PD-1 approaches. SIGNIFICANCE:
The benefit of 5-FU/platinum with anti-PD-1 in first-line advanced gastric cancer is limited to patient subgroups. Using a trial with sequential anti-PD-1, we show coordinated induction of multicellular TME hubs informs the ability of anti-PD-1 to potentiate T cell-driven responses. Differential TME hub development highlights features that underlie clinical outcomes. This article is featured in Selected Articles from This Issue, p. 695.
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Neoplasias Gástricas
/
Microambiente Tumoral
Límite:
Aged
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Female
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Humans
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Male
/
Middle aged
Idioma:
En
Revista:
Cancer Discov
Año:
2024
Tipo del documento:
Article
Pais de publicación:
Estados Unidos