Geospatial characterization of immune cell distributions and dynamics across the microenvironment in clear cell renal cell carcinoma Journal Article


Authors: Chakiryan, N. H.; Kim, Y.; Berglund, A.; Chang, A.; Kimmel, G. J.; Hajiran, A.; Nguyen, J.; Moran-Segura, C.; Saeed-Vafa, D.; Katende, E. N.; Lopez-Blanco, N.; Chahoud, J.; Rappold, P.; Spiess, P. E.; Fournier, M.; Jeong, D.; Wang, L.; Teer, J. K.; Dhillon, J.; Kuo, F.; Hakimi, A. A.; Altrock, P. M.; Mulé, J. J.; Manley, B. J.
Article Title: Geospatial characterization of immune cell distributions and dynamics across the microenvironment in clear cell renal cell carcinoma
Abstract: Introduction In clear cell renal cell carcinoma (ccRCC), tumor-associated macrophage (TAM) induction of CD8+T cells into a terminally exhausted state has been implicated as a major mechanism of immunotherapy resistance, but a deeper biological understanding is necessary. Methods Primary ccRCC tumor samples were obtained from 97 patients between 2004 and 2018. Multiplex immunofluorescence using lymphoid and myeloid markers was performed in seven regions of interest per patient across three predefined zones, and geospatial analysis was performed using Ripley's K analysis, a methodology adapted from ecology. Results Clustering of CD163+M2 like TAMs into the stromal compartment at the tumor-stroma interface was associated with worse clinical stage (tumor/CD163+nK(75): stage I/II: 4.4 (IQR -0.5 to 5.1); stage III: 1.4 (IQR -0.3 to 3.5); stage IV: 0.6 (IQR -2.1 to 2.1); p=0.04 between stage I/II and stage IV), and worse overall survival (OS) and cancer-specific survival (CSS) (tumor/CD163+nK(75): median OS-hi=149 months, lo=86 months, false-discovery rate (FDR)-adj. Cox p<0.001; median CSS-hi=174 months, lo=85 months; FDR-adj. Cox p<0.001). An RNA-seq differential gene expression score was developed using this geospatial metric, and was externally validated in multiple independent cohorts of patients with ccRCC including: TCGA KIRC, and the IMmotion151, IMmotion150, and JAVELIN Renal 101 clinical trials. In addition, this CD163+ geospatial pattern was found to be associated with a higher TIM-3+ proportion of CD8+T cells, indicative of terminal exhaustion (tumor-core: 0.07 (IQR 0.04-0.14) vs 0.40 (IQR 0.15-0.66), p=0.05). Conclusions Geospatial clustering of CD163+M2 like TAMs into the stromal compartment at the tumor-stromal interface was associated with poor clinical outcomes and CD8+T cell terminal exhaustion. © 2023 BMJ Publishing Group. All rights reserved.
Keywords: adult; controlled study; human tissue; aged; major clinical study; overall survival; bevacizumab; sunitinib; sensitivity analysis; cd8+ t lymphocyte; cd8-positive t-lymphocytes; image analysis; immunofluorescence; angiogenesis; retrospective study; renal cell carcinoma; kidney neoplasms; immunotherapy; kidney tumor; carcinoma, renal cell; cancer specific survival; cellular distribution; cell density; microenvironment; macrophages; dynamics; immunocompetent cell; recurrence free survival; clear cell renal cell carcinoma; tumor microenvironment; tumor-associated macrophage; antigen retrieval; fluorescence intensity; humans; prognosis; human; male; female; article; rna sequencing; differential gene expression; atezolizumab
Journal Title: Journal for ImmunoTherapy of Cancer
Volume: 11
Issue: 4
ISSN: 2051-1426
Publisher: Biomed Central Ltd  
Date Published: 2023-04-01
Start Page: e006195
Language: English
DOI: 10.1136/jitc-2022-006195
PUBMED: 37185232
PROVIDER: scopus
PMCID: PMC10151991
DOI/URL:
Notes: Article -- Export Date: 1 June 2023 -- Source: Scopus
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MSK Authors
  1. Abraham Ari Hakimi
    295 Hakimi
  2. Fengshen Kuo
    64 Kuo