Aristolochic acid-related renal cell carcinoma exhibits a distinct tumor-immune microenvironment favoring response to immune checkpoint blockade.

Autor: Lin PH; Division of Urology, Department of Surgery, Chang Gung Memorial Hospital at Linkou, Taoyuan, Taiwan.; Graduate Institute of Clinical Medical Science, College of Medicine, Chang Gung University, Taoyuan, Taiwan.; School of Medicine, College of Medicine, Chang Gung University, Taoyuan, Taiwan., Chan JY; Cancer Discovery Hub, National Cancer Centre Singapore, Singapore, Singapore., Guan P; Genome Institute of Singapore, Agency for Science, Technology and Research (A*STAR), Singapore, Singapore., Hong JH; Cancer and Stem Cell Biology Programme, Duke-NUS Medical School, Singapore, Singapore., Lim AH; Cancer Discovery Hub, National Cancer Centre Singapore, Singapore, Singapore., Ng CC; Cancer Discovery Hub, National Cancer Centre Singapore, Singapore, Singapore., Yeong JPS; Integrative Biology for Theranostics Lab, Cancer Signaling & Therapies Programme, Institute of Molecular and Cell Biology, Singapore, Singapore.; Department of Anatomical Pathology, Singapore General Hospital, Singapore, Singapore.; Pathology Academic Clinical Program, Duke-NUS Medical School, Singapore, Singapore.; Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore., Lee JY; Cancer Discovery Hub, National Cancer Centre Singapore, Singapore, Singapore., Liu W; Laboratory of Cancer Epigenome, Division of Medical Science, National Cancer Centre Singapore, Singapore, Singapore., Lim JCT; Integrative Biology for Theranostics Lab, Cancer Signaling & Therapies Programme, Institute of Molecular and Cell Biology, Singapore, Singapore., Pang ST; Division of Urology, Department of Surgery, Chang Gung Memorial Hospital at Linkou, Taoyuan, Taiwan.; School of Medicine, College of Medicine, Chang Gung University, Taoyuan, Taiwan., Teh BT; Genome Institute of Singapore, Agency for Science, Technology and Research (A*STAR), Singapore, Singapore.; Cancer and Stem Cell Biology Programme, Duke-NUS Medical School, Singapore, Singapore.; Laboratory of Cancer Epigenome, Division of Medical Science, National Cancer Centre Singapore, Singapore, Singapore.; Institute of Molecular and Cell Biology, Agency for Science, Technology and Research (A*STAR), Singapore, Singapore.
Jazyk: angličtina
Zdroj: The Journal of pathology [J Pathol] 2024 Oct 03. Date of Electronic Publication: 2024 Oct 03.
DOI: 10.1002/path.6349
Abstrakt: Immune checkpoint blockade (ICB) is currently the standard of care for metastatic renal cell carcinoma (RCC), but treatment responses remain unpredictable. Aristolochic acid (AA), a prevalent supplement additive in Taiwan, has been associated with RCC and induces signature mutations, although its effect on the tumor-immune microenvironment (TIME) is unclear. We aimed to investigate the immune profile of AA-positive RCCs and explore its potential role as a susceptible candidate for ICB. Tissue samples from 22 patients with clear cell RCC (ccRCC) were collected for whole-exome sequencing to determine the genetic features and AA mutational signature (the discovery cohort). The corresponding RNA was sent for NanoString PanCancer IO 360 gene expression analysis to explore the immunological features. The formalin-fixed, parafilm-embedded slides of ccRCCs were sent for multiplex immunohistochemistry/immunofluorescence stain using Vectra system to evaluate the TIME. Tissues from two patients with metastatic RCC demonstrating complete response to ICB were sent for studies to validate the findings (the index patients). The results showed that AA mutational signatures with high tumor mutational burden (TMB) were present in 31.81% of the tumors in the discovery cohort. Three distinct clusters were observed through NanoString analysis. Clusters 1 and 3 were composed mainly of AA-positive RCCs. Cluster 3 RCCs exhibited higher tumor inflammation signature scores and higher immune cell type scores. Vectra analysis revealed a higher percentage of CD15+ and BATF3+ cells in cluster 1, whereas the percentage of CD8+ cells was potentially higher in cluster 3. Strong AA mutational signatures were found in the tumors of two index patients, and both were grouped to cluster 3. In conclusion, AA may induce higher TMB and alter the immune microenvironment in RCCs, which makes the tumors more susceptible to ICB. © 2024 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.
(© 2024 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.)
Databáze: MEDLINE
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