Single-cell Transcriptomics Reveals Antigen-presenting Capacity and Therapeutic Resistance Potential of Immunomodulatory Endothelial Cells in Colorectal Cancer

Overview

Journal Immun Inflamm Dis

Specialties Allergy & Immunology
Infectious Diseases

Date 2024 Jun 14

PMID 38874280

Authors

Jingyi Wen

Affiliations

Soon will be listed here.

Abstract

Background: The heterogeneity of tumor endothelial cells (TECs) hinders the efficacy of antiangiogenic therapies (AATs). Only a small percentage of angiogenic TECs are considered effective targets for AATs. Immunomodulatory ECs (IMECs), as a newly focused functional subgroup of endothelial cells (ECs), are being evaluated for their ability to regulate tumor immune balance and influence existing AATs.

Methods: Based on single-cell transcriptome data from colorectal cancer in a publicly available database, we conducted a wide array of bioinformatic approaches to study EC subsets that meet the IMECs definition. Our investigation encompassed the gene expression signatures of these subsets, cellular composition differences, cell-cell interactions.

Results: Two subsets that meet the IMECs definition were found in tumors and para-cancerous tissues. Combined with the results of gene ontological analysis and interaction with CD4 T cells, we found that IMECs can present MHC-II antigens to mature CD4 T cells. There were differences in the level of interaction between IMECs and different types of mature CD4 T cell subsets. In addition, IMEC subsets had different expression levels of angiogenesis related genes. The angiogenesis score of IMECs decreased after patients received immunotherapy. IMEC subsets do not depend on a single proangiogenic receptor and are involved in regulating angiogenesis, which may reduce the efficacy of AATs. The adverse effects of specific IMEC subsets on AATs were validated in the RNA-seq dataset of the bevacizumab treatment group.

Conclusion: Our study suggests the potential MHC-II antigen presentation capacity of IMECs and the enhanced angiogenesis characteristics within tumors. The function of IMECs in the vascular network may have a potentially adverse effect on AATs. Controlling the functional properties of IMECs may be a new angle for tumor therapy.

References

Huang D, Sherman B, Lempicki R . Systematic and integrative analysis of large gene lists using DAVID bioinformatics resources. Nat Protoc. 2009; 4(1):44-57. DOI: 10.1038/nprot.2008.211. View

Saio S, Konishi K, Hohjoh H, Tamura Y, Masutani T, Iddamalgoda A . Extracellular Environment-Controlled Angiogenesis, and Potential Application for Peripheral Nerve Regeneration. Int J Mol Sci. 2021; 22(20). PMC: 8541280. DOI: 10.3390/ijms222011169. View

Denisenko E, Guo B, Jones M, Hou R, de Kock L, Lassmann T . Systematic assessment of tissue dissociation and storage biases in single-cell and single-nucleus RNA-seq workflows. Genome Biol. 2020; 21(1):130. PMC: 7265231. DOI: 10.1186/s13059-020-02048-6. View

de Heer E, Jalving M, Harris A . HIFs, angiogenesis, and metabolism: elusive enemies in breast cancer. J Clin Invest. 2020; 130(10):5074-5087. PMC: 7524491. DOI: 10.1172/JCI137552. View

Zhang Y, Chen H, Mo H, Hu X, Gao R, Zhao Y . Single-cell analyses reveal key immune cell subsets associated with response to PD-L1 blockade in triple-negative breast cancer. Cancer Cell. 2021; 39(12):1578-1593.e8. DOI: 10.1016/j.ccell.2021.09.010. View

Guo N, Wen Y, Wang C, Kang L, Wang X, Liu X . Lung adenocarcinoma-related TNF-α-dependent inflammation upregulates MHC-II on alveolar type II cells through CXCR-2 to contribute to Treg expansion. FASEB J. 2020; 34(9):12197-12213. DOI: 10.1096/fj.202000166RR. View

Zhang Z, Ji S, Zhang B, Liu J, Qin Y, Xu J . Role of angiogenesis in pancreatic cancer biology and therapy. Biomed Pharmacother. 2018; 108:1135-1140. DOI: 10.1016/j.biopha.2018.09.136. View

Poisson J, Lemoinne S, Boulanger C, Durand F, Moreau R, Valla D . Liver sinusoidal endothelial cells: Physiology and role in liver diseases. J Hepatol. 2016; 66(1):212-227. DOI: 10.1016/j.jhep.2016.07.009. View

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

10.

Chen J, Fu Y, Day D, Sun Y, Wang S, Liang X . VEGF amplifies transcription through ETS1 acetylation to enable angiogenesis. Nat Commun. 2017; 8(1):383. PMC: 5575285. DOI: 10.1038/s41467-017-00405-x. View

11.

Zhang F, Li X, Tian W . Unsupervised Inference of Developmental Directions for Single Cells Using VECTOR. Cell Rep. 2020; 32(8):108069. DOI: 10.1016/j.celrep.2020.108069. View

12.

He Y, Lin L, Ou Y, Hu X, Xu C, Wang C . Endothelial cell-specific molecule 1 (ESM1) promoted by transcription factor SPI1 acts as an oncogene to modulate the malignant phenotype of endometrial cancer. Open Med (Wars). 2022; 17(1):1376-1389. PMC: 9420884. DOI: 10.1515/med-2022-0529. View

13.

Conforti F, Zucali P, Pala L, Catania C, Bagnardi V, Sala I . Avelumab plus axitinib in unresectable or metastatic type B3 thymomas and thymic carcinomas (CAVEATT): a single-arm, multicentre, phase 2 trial. Lancet Oncol. 2022; 23(10):1287-1296. DOI: 10.1016/S1470-2045(22)00542-3. View

14.

Choueiri T, Larkin J, Oya M, Thistlethwaite F, Martignoni M, Nathan P . Preliminary results for avelumab plus axitinib as first-line therapy in patients with advanced clear-cell renal-cell carcinoma (JAVELIN Renal 100): an open-label, dose-finding and dose-expansion, phase 1b trial. Lancet Oncol. 2018; 19(4):451-460. DOI: 10.1016/S1470-2045(18)30107-4. View

15.

Qin S, Li A, Yi M, Yu S, Zhang M, Wu K . Recent advances on anti-angiogenesis receptor tyrosine kinase inhibitors in cancer therapy. J Hematol Oncol. 2019; 12(1):27. PMC: 6417086. DOI: 10.1186/s13045-019-0718-5. View

16.

Cheng N, Brantley D, Fang W, Liu H, Fanslow W, Cerretti D . Inhibition of VEGF-dependent multistage carcinogenesis by soluble EphA receptors. Neoplasia. 2003; 5(5):445-56. PMC: 1502614. DOI: 10.1016/s1476-5586(03)80047-7. View

17.

Sharma A, Seow J, Dutertre C, Pai R, Bleriot C, Mishra A . Onco-fetal Reprogramming of Endothelial Cells Drives Immunosuppressive Macrophages in Hepatocellular Carcinoma. Cell. 2020; 183(2):377-394.e21. DOI: 10.1016/j.cell.2020.08.040. View

18.

Sherman B, Hao M, Qiu J, Jiao X, Baseler M, Lane H . DAVID: a web server for functional enrichment analysis and functional annotation of gene lists (2021 update). Nucleic Acids Res. 2022; 50(W1):W216-W221. PMC: 9252805. DOI: 10.1093/nar/gkac194. View

19.

Wu T, Hu E, Xu S, Chen M, Guo P, Dai Z . clusterProfiler 4.0: A universal enrichment tool for interpreting omics data. Innovation (Camb). 2021; 2(3):100141. PMC: 8454663. DOI: 10.1016/j.xinn.2021.100141. View

20.

Xue R, Zhang Q, Cao Q, Kong R, Xiang X, Liu H . Liver tumour immune microenvironment subtypes and neutrophil heterogeneity. Nature. 2022; 612(7938):141-147. DOI: 10.1038/s41586-022-05400-x. View