journal contribution
posted on 2024-05-01, 07:41 authored by Minae An, Arnav Mehta, Byung Hoon Min, You Jeong Heo, Samuel J. Wright, Milan Parikh, Lynn Bi, Hyuk Lee, Tae Jun Kim, Song-Yi Lee, Jeonghyeon Moon, Ryan J. Park, Matthew R. Strickland, Woong-Yang Park, Won Ki Kang, Kyoung-Mee Kim, Seung Tae Kim, Samuel J. Klempner, Jeeyun Lee Figure S19. (A) UMAP embedding of single cell transcriptomes of all
macrophages obtained from all samples in this trial. Labeled are granular
macrophage subsets separated by tumor v.s. normal tissue, and by timepoint. (B)
UMAP embeddings showing marker gene expression for macrophage subsets in
(A). (C) Relative M1 macrophage proportion in fast and slow progressing patients
separated by timepoint. (D) Macrophage subtype proportions at baseline and FU1
in fast versus slow progressing patients, and in non-responder and responder
patients. (E) Relative M1 macrophage proportion in non-responder and responder
patients separated by timepoint. (F) Proportion of SPP1+ macrophages in nonresponder
and responder patients split by timepoint. Statistical comparisons
performed using a Wilcoxon signed-rank test. (G) Change in relative M1
proportion from BL to FU1 plotted against change in tumor volume after 1 cycle of
chemotherapy, segregated by non-responder and responder patients. (H) GSVA
performed for M2 signatures on bulk RNA-seq samples split by timepoints and
progression status.
Funding
Doris Duke Charitable Foundation (DDCF)
DeGregorio Family Foundation (DFF)
Stand Up To Cancer (SU2C)
Korea Health Industry Development Institute (KHIDI)
Sungkyunkwan University (SKKU)
History
ARTICLE 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.
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
