Genetic and Therapeutic Heterogeneity Shape the Baseline and Longitudinal Immune Ecosystem of Ovarian Clear Cell Carcinoma

Overview

Journal J Immunother Cancer

Specialties Allergy & Immunology
Oncology
Pharmacology

Date 2024 Nov 28

PMID 39608974

Authors

Siyu Xia

Lihua Chen

Min Yu

Jiana Li

Jiaxin Chen

Fei Xu

Mengdong Ni

Chaohua Liu

Xiaohua Wu

Xiaojun Chen

Jiajia Li

Affiliations

Soon will be listed here.

Abstract

Background: Ovarian clear cell carcinoma (OCCC) is a rare and chemo-resistant subtype of ovarian cancer. While immunotherapy has demonstrated effectiveness in some OCCC cases, the mechanisms for heterogeneous immunoreactivity and potential combinatory strategies remain unclear.

Methods: Tumor samples from 13 patients with OCCC underwent single-cell mRNA-seq and TCR-seq to generate 1 40 683 cells transcriptome, while additionally 31 formalin-fixed paraffin-embedded samples were used for immunohistochemistry. Spatial transcriptomics of two OCCC samples and bulk RNA-seq of 58 patients were incorporated for spatial and interpatient level explorations. Serum tumor markers and radiologic images of three patients with OCCC who received combinatory VEGF and PD-1 inhibition were retrospectively analyzed.

Results: OCCC exhibited a dynamic immune architecture shaped by genetic and therapeutic pressure. mutation linked to baseline immune activation, correlated with an enrichment of neoantigen-reactive CXCL13 CTLA4 CD8 T cells (p<0.001) and enhanced FASLG-FAS interactions. Recurrent OCCC was fibrotic, angiogenic, and immunosuppressive, exhibiting metabolic reprogramming towards activated activity in fatty acid metabolism. High CD36 (log-rank p=0.012, HR: 4.515) and CD47 expression (log-rank p=0.037, HR: 3.246) indicated worse progression-free survival. Treatment with bevacizumab increased intratumoral T cell infiltration and activated T cell interferon-γ signaling. Retrospective analysis of clinical cases revealed that combination therapy with anti-VEGF (vascular endothelial growth factor) and anti-PD-1 agents exerted clinical benefits in patients with OCCC with persistent, recurrent, and metastatic disease.

Conclusions: mutation correlated with OCCC baseline immune activation. Stromal reconstruction and tumor metabolic reprogramming functioned as key processes of OCCC dynamic progression. VEGF inhibition remodeled OCCC stroma, restored T cell function and potentiated immunotherapy. CD36 and CD47 might be potential therapeutic targets for recurrent OCCC.

Citing Articles

Infiltration of CD8 cytotoxic T-cells and expression of PD-1 and PD-L1 in ovarian clear cell carcinoma.

Fu M, Zhou H, Yang J, Cao D, Yuan Z Sci Rep. 2025; 15(1):4716.

PMID: 39922892 PMC: 11807128. DOI: 10.1038/s41598-025-89270-z.

References

Street K, Risso D, Fletcher R, Das D, Ngai J, Yosef N . Slingshot: cell lineage and pseudotime inference for single-cell transcriptomics. BMC Genomics. 2018; 19(1):477. PMC: 6007078. DOI: 10.1186/s12864-018-4772-0. View

Gyorffy B . Discovery and ranking of the most robust prognostic biomarkers in serous ovarian cancer. Geroscience. 2023; 45(3):1889-1898. PMC: 10400493. DOI: 10.1007/s11357-023-00742-4. View

Sung H, Ferlay J, Siegel R, Laversanne M, Soerjomataram I, Jemal A . Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA Cancer J Clin. 2021; 71(3):209-249. DOI: 10.3322/caac.21660. View

Frentzas S, Mislang A, Lemech C, Nagrial A, Underhill C, Wang W . Phase 1a dose escalation study of ivonescimab (AK112/SMT112), an anti-PD-1/VEGF-A bispecific antibody, in patients with advanced solid tumors. J Immunother Cancer. 2024; 12(4). PMC: 11033648. DOI: 10.1136/jitc-2023-008037. View

Mori Y, Okimoto Y, Sakai H, Kanda Y, Ohata H, Shiokawa D . Targeting PDGF signaling of cancer-associated fibroblasts blocks feedback activation of HIF-1α and tumor progression of clear cell ovarian cancer. Cell Rep Med. 2024; 5(5):101532. PMC: 11149410. DOI: 10.1016/j.xcrm.2024.101532. View

Suehnholz S, Nissan M, Zhang H, Kundra R, Nandakumar S, Lu C . Quantifying the Expanding Landscape of Clinical Actionability for Patients with Cancer. Cancer Discov. 2023; 14(1):49-65. PMC: 10784742. DOI: 10.1158/2159-8290.CD-23-0467. View

Calo C, Levine M, Brown M, OMalley D, Backes F . Combination lenvatinib plus pembrolizumab in the treatment of ovarian clear cell carcinoma: A case series. Gynecol Oncol Rep. 2023; 46:101171. PMC: 10090985. DOI: 10.1016/j.gore.2023.101171. View

Han G, Sinjab A, Rahal Z, Lynch A, Treekitkarnmongkol W, Liu Y . An atlas of epithelial cell states and plasticity in lung adenocarcinoma. Nature. 2024; 627(8004):656-663. PMC: 10954546. DOI: 10.1038/s41586-024-07113-9. View

Badia-I-Mompel P, Velez Santiago J, Braunger J, Geiss C, Dimitrov D, Muller-Dott S . decoupleR: ensemble of computational methods to infer biological activities from omics data. Bioinform Adv. 2023; 2(1):vbac016. PMC: 9710656. DOI: 10.1093/bioadv/vbac016. View

10.

Bolton K, Chen D, Corona de la Fuente R, Fu Z, Murali R, Kobel M . Molecular Subclasses of Clear Cell Ovarian Carcinoma and Their Impact on Disease Behavior and Outcomes. Clin Cancer Res. 2022; 28(22):4947-4956. PMC: 9777703. DOI: 10.1158/1078-0432.CCR-21-3817. View

11.

Ghisoni E, Morotti M, Sarivalasis A, Grimm A, Kandalaft L, Dangaj Laniti D . Immunotherapy for ovarian cancer: towards a tailored immunophenotype-based approach. Nat Rev Clin Oncol. 2024; 21(11):801-817. DOI: 10.1038/s41571-024-00937-4. View

12.

Iida Y, Okamoto A, Hollis R, Gourley C, Herrington C . Clear cell carcinoma of the ovary: a clinical and molecular perspective. Int J Gynecol Cancer. 2020; 31(4):605-616. DOI: 10.1136/ijgc-2020-001656. View

13.

Itamochi H, Kigawa J, Terakawa N . Mechanisms of chemoresistance and poor prognosis in ovarian clear cell carcinoma. Cancer Sci. 2008; 99(4):653-8. PMC: 11158134. DOI: 10.1111/j.1349-7006.2008.00747.x. View

14.

Matulonis U, Shapira-Frommer R, Santin A, Lisyanskaya A, Pignata S, Vergote I . Antitumor activity and safety of pembrolizumab in patients with advanced recurrent ovarian cancer: results from the phase II KEYNOTE-100 study. Ann Oncol. 2019; 30(7):1080-1087. DOI: 10.1093/annonc/mdz135. View

15.

Ledermann J, Shapira-Frommer R, Santin A, Lisyanskaya A, Pignata S, Vergote I . Molecular determinants of clinical outcomes of pembrolizumab in recurrent ovarian cancer: Exploratory analysis of KEYNOTE-100. Gynecol Oncol. 2023; 178:119-129. DOI: 10.1016/j.ygyno.2023.09.012. View

16.

Hamzah J, Jugold M, Kiessling F, Rigby P, Manzur M, Marti H . Vascular normalization in Rgs5-deficient tumours promotes immune destruction. Nature. 2008; 453(7193):410-4. DOI: 10.1038/nature06868. View

17.

Shu C, Zhou Q, Jotwani A, Iasonos A, Leitao Jr M, Konner J . Ovarian clear cell carcinoma, outcomes by stage: the MSK experience. Gynecol Oncol. 2015; 139(2):236-41. PMC: 4632203. DOI: 10.1016/j.ygyno.2015.09.016. View

18.

Brahmer J, Tykodi S, Chow L, Hwu W, Topalian S, Hwu P . Safety and activity of anti-PD-L1 antibody in patients with advanced cancer. N Engl J Med. 2012; 366(26):2455-65. PMC: 3563263. DOI: 10.1056/NEJMoa1200694. View

19.

Feig C, Jones J, Kraman M, Wells R, Deonarine A, Chan D . Targeting CXCL12 from FAP-expressing carcinoma-associated fibroblasts synergizes with anti-PD-L1 immunotherapy in pancreatic cancer. Proc Natl Acad Sci U S A. 2013; 110(50):20212-7. PMC: 3864274. DOI: 10.1073/pnas.1320318110. View

20.

Zboralski D, Hoehlig K, Eulberg D, Fromming A, Vater A . Increasing Tumor-Infiltrating T Cells through Inhibition of CXCL12 with NOX-A12 Synergizes with PD-1 Blockade. Cancer Immunol Res. 2017; 5(11):950-956. DOI: 10.1158/2326-6066.CIR-16-0303. View