Reconstruction of the gastric cancer microenvironment after neoadjuvant chemotherapy by longitudinal single-cell sequencing

Yingtai Chen; Jianhua Yin; Lulu Zhao; Guangyu Zhou; Shichen Dong; Yueming Zhang; Penghui Niu; Hu Ren; Tianjiao Zheng; Juan Yan; Wenbin Li; Peiqin Ma; Cuijuan Zhang; Chen Wei; George Church; Guibo Li; Dongbing Zhao

doi:10.1186/s12967-022-03792-y

Reconstruction of the gastric cancer microenvironment after neoadjuvant chemotherapy by longitudinal single-cell sequencing

J Transl Med. 2022 Dec 6;20(1):563. doi: 10.1186/s12967-022-03792-y.

Authors

Yingtai Chen^#¹, Jianhua Yin^#^{2

3

4}, Lulu Zhao^#¹, Guangyu Zhou^#^{5

6}, Shichen Dong^#^{2

3

4}, Yueming Zhang^#¹, Penghui Niu^#¹, Hu Ren^#¹, Tianjiao Zheng^{2

3

4}, Juan Yan^{2

3

4}, Wenbin Li¹, Peiqin Ma¹, Cuijuan Zhang^{2

3

4}, Chen Wei^{2

3

4

7}, George Church^{8

9

10}, Guibo Li^{11

12

13

14}, Dongbing Zhao¹⁵

Affiliations

¹ National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, 17 Panjiayuan Nanli, Beijing, 100021, China.
² BGI-Shenzhen, Shenzhen, 518083, Guangdong, China.
³ BGl College & Henan Institute of Medical and Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, 450001, Henan, China.
⁴ BGI-Henan, Xinxiang, 453000, Henan, China.
⁵ Department of Genetics, Harvard Medical School, Boston, MA, 02115, USA.
⁶ Department of Molecular and Cellular Biology, Harvard University, Cambridge, MA, 02138, USA.
⁷ BGI Education Center, University of Chinese Academy of Sciences, Shenzhen, 518083, China.
⁸ Department of Genetics, Harvard Medical School, Boston, MA, 02115, USA. gchurch@genetics.med.harvard.edu.
⁹ Department of Molecular and Cellular Biology, Harvard University, Cambridge, MA, 02138, USA. gchurch@genetics.med.harvard.edu.
¹⁰ Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, MA, 02115, USA. gchurch@genetics.med.harvard.edu.
¹¹ BGI-Shenzhen, Shenzhen, 518083, Guangdong, China. liguibo@genomics.cn.
¹² BGl College & Henan Institute of Medical and Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, 450001, Henan, China. liguibo@genomics.cn.
¹³ BGI-Henan, Xinxiang, 453000, Henan, China. liguibo@genomics.cn.
¹⁴ Shenzhen Key Laboratory of Single-Cell Omics, BGI Shenzhen, Shenzhen, 518120, Guangdong, China. liguibo@genomics.cn.
¹⁵ National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, 17 Panjiayuan Nanli, Beijing, 100021, China. dbzhao@cicams.ac.cn.

^# Contributed equally.

Abstract

Background: Little is known on the tumor microenvironment (TME) response after neoadjuvant chemotherapy (NACT) in gastric cancer on the molecular level.

Methods: Here, we profiled 33,589 cell transcriptomes in 14 samples from 11 gastric cancer patients (4 pre-treatment samples, 4 post-treatment samples and 3 pre-post pairs) using single-cell RNA sequencing (scRNA-seq) to generate the cell atlas. The ligand-receptor-based intercellular communication networks of the single cells were also characterized before and after NACT.

Results: Compered to pre-treatment samples, CD4+ T cells (P = 0.018) and CD8+ T cells (P = 0.010) of post-treatment samples were significantly decreased, while endothelial cells and fibroblasts were increased (P = 0.034 and P = 0.005, respectively). No significant difference observed with respect to CD4+ Tregs cells, cycling T cells, B cells, plasma cells, macrophages, monocytes, dendritic cells, and mast cells (P > 0.05). In the unsupervised nonnegative matrix factorization (NMF) analysis, we revealed that there were three transcriptional programs (NMF1, NMF2 and NMF3) shared among these samples. Compared to pre-treatment samples, signature score of NMF1 was significantly downregulated after treatment (P = 0.009), while the NMF2 signature was significantly upregulated after treatment (P = 0.013). The downregulated NMF1 and upregulated NMF2 signatures were both associated with improved overall survival outcomes based on The Cancer Genome Atlas (TCGA) database. Additionally, proangiogenic pathways were activated in tumor and endothelial cells after treatment, indicating that NACT triggers vascular remodeling by cancer cells together with stromal cells.

Conclusions: In conclusion, our study provided transcriptional profiles of TME between pre-treatment and post-treatment for in-depth understanding on the mechanisms of NACT in gastric cancer and empowering the development of potential optimized therapy procedures and novel drugs.

Keywords: Gastric cancer; Neoadjuvant chemotherapy (NACT); Single-cell RNA sequencing.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Endothelial Cells
Humans
Neoadjuvant Therapy
Stomach Neoplasms* / drug therapy
Stomach Neoplasms* / genetics
Tumor Microenvironment*