Integrated proteomics and scRNA-seq analyses of ovarian cancer reveal molecular subtype-associated cell landscapes and immunotherapy targets

Rong Tan; Ming Wen; Wenqing Yang; Dongdong Zhan; Nairen Zheng; Mingwei Liu; Fang Zhu; Xiaodan Chen; Meng Wang; Siyu Yang; Bin Xie; Qiongqiong He; Kai Yuan; Lunquan Sun; Yi Wang; Jun Qin; Yu Zhang

doi:10.1038/s41416-024-02894-2

Integrated proteomics and scRNA-seq analyses of ovarian cancer reveal molecular subtype-associated cell landscapes and immunotherapy targets

Br J Cancer. 2024 Nov 15. doi: 10.1038/s41416-024-02894-2. Online ahead of print.

Authors

Rong Tan^#^{1

2

3

4

5}, Ming Wen^#^{6

7

8

9

10}, Wenqing Yang^{6

9

11}, Dongdong Zhan^{12

13}, Nairen Zheng¹², Mingwei Liu¹², Fang Zhu^{6

11}, Xiaodan Chen^{6

11}, Meng Wang^{7

8}, Siyu Yang^{6

11}, Bin Xie^{14

15}, Qiongqiong He^{14

15}, Kai Yuan^{9

16}, Lunquan Sun^{7

8

9

16

17}, Yi Wang¹⁸, Jun Qin^{19

20}, Yu Zhang^{21

22

23}

Affiliations

¹ Department of Gynecology, Xiangya Hospital, Central South University, Changsha, Hunan, China. rongtan@csu.edu.cn.
² Xiangya Cancer Center, Xiangya Hospital, Central South University, Changsha, China. rongtan@csu.edu.cn.
³ Key Laboratory of Molecular Radiation Oncology Hunan Province, Changsha, China. rongtan@csu.edu.cn.
⁴ National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China. rongtan@csu.edu.cn.
⁵ Hunan key laboratory of aging biology, Xiangya Hospital, Central South University, Changsha, China. rongtan@csu.edu.cn.
⁶ Department of Gynecology, Xiangya Hospital, Central South University, Changsha, Hunan, China.
⁷ Xiangya Cancer Center, Xiangya Hospital, Central South University, Changsha, China.
⁸ Key Laboratory of Molecular Radiation Oncology Hunan Province, Changsha, China.
⁹ National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China.
¹⁰ Hunan key laboratory of aging biology, Xiangya Hospital, Central South University, Changsha, China.
¹¹ Gynecological Oncology Research and Engineering Center of Hunan Province, Changsha, Hunan, China.
¹² State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences (Beijing), Beijing Institute of Lifeomics, Beijing, China.
¹³ Beijing Pineal Diagnostics Co., Ltd., Beijing, China.
¹⁴ Department of Pathology, Xiangya Hospital, Central South University, Changsha, Hunan, China.
¹⁵ Department of Pathology, School of Basic Medicine, Central South University, Changsha, Hunan, China.
¹⁶ Hunan International Science and Technology Collaboration Base of Precision Medicine for Cancer, Changsha, China.
¹⁷ Center for Molecular Imaging of Central South University, Xiangya Hospital, Changsha, China.
¹⁸ State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences (Beijing), Beijing Institute of Lifeomics, Beijing, China. wangyi@ncpsb.org.cn.
¹⁹ State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences (Beijing), Beijing Institute of Lifeomics, Beijing, China. qinjun@ncpsb.org.cn.
²⁰ State Key Laboratory of Genetic Engineering and Collaborative Innovation Center for Genetics and Development, School of Life Sciences, Institute of Biomedical Sciences, Fudan University, Shanghai, China. qinjun@ncpsb.org.cn.
²¹ Department of Gynecology, Xiangya Hospital, Central South University, Changsha, Hunan, China. xyzhangyu@csu.edu.cn.
²² National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China. xyzhangyu@csu.edu.cn.
²³ Gynecological Oncology Research and Engineering Center of Hunan Province, Changsha, Hunan, China. xyzhangyu@csu.edu.cn.

^# Contributed equally.

PMID: 39548315
DOI: 10.1038/s41416-024-02894-2

Abstract

Background: Epithelial ovarian cancer (EOC) represents the most lethal gynaecological malignancy, yet understanding the connections between its molecular subtypes and their therapeutic implications remains incomplete.

Methods: We conducted mass spectrometry-based proteomics analyses of 154 EOC tumour samples and 29 normal fallopian tubes, and single-cell RNA sequencing (scRNA-seq) analyses of an additional eight EOC tumours to classify proteomic subtypes and assess their cellular ecosystems and clinical significance. The efficacy of identified therapeutic targets was evaluated in patient-derived xenograft (PDX) and orthotopic mouse models.

Results: We identified four proteomic subtypes with distinct clinical relevance: malignant proliferative (C1), immune infiltrating (C2), Fallopian-like (C3) and differentiated (C4) subtypes. C2 subtype was characterized by lymphocyte infiltration, notably an increased presence of GZMK CD8+ T cells and phagocytosis-like MRC+ macrophages. Additionally, we identified CD40 as a specific prognostic factor for C2 subtype. The interaction between CD40+ phagocytosis-like macrophages and CD40RL+ IL17R CD4+ T cells was correlated with a favourable prognosis. Finally, we established a druggable landscape for non-immune EOC patients and verified a TYMP inhibitor as a promising therapeutic strategy.

Conclusions: Our study refines the current immune subtype for EOC, highlighting CD40 agonists as promising therapies for C2 subtype patients and targeting TYMP for non-immune patients.

Abstract

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