Study reveals spatial heterogeneity in the tumor microenvironment of multiregional clear cell renal cell carcinoma biopsies

BostonGene Corporation announced the publication of a study, conducted in collaboration with researchers at Washington University School of Medicine in St. Louis, that revealed intratumor spatial heterogeneity (ITH) occurs in clear cell renal cell carcinoma (ccRCC), which may drive clinical heterogeneity and warrants further investigation to improve patient outcomes.

To dissect ITH in ccRCC, BostonGene studied tumor samples from Washington University, performing multiregional tumor analyses using a multi-dimensional and integrated approach encompassing myriad technologies at both the single-cell level with mass cytometry (CyTOF), multiplex immunofluorescence (MxIF), single nuclei RNA-seq (snRNA-seq) and bulk level whole exome sequencing (WES), RNA sequencing (RNA-seq) and methylation profiling.

Multiregional analyses revealed unexpected conservation of immune composition of the tumor microenvironment (TME) within each patient, with profound differences found among patients. Despite genetic heterogeneity from clonal evolution, patient-specific immune TME signatures were identified and confirmed by MxIF cell phenotyping and BostonGene’s RNA-seq deconvolution algorithm, Kassandra. Further MxIF analysis showed striking spatial architectural heterogeneity among different regions of the same tumor, revealing the presence of diverse cellular neighborhoods.

By coupling experimental tools, including multiomic profiling and multiplex imaging, with artificial intelligence-driven analytics, we dissected the complex tumor ecosystem at different hierarchical levels, providing insights into both ITH and clinical heterogeneity in ccRCC.

“The research conducted with Washington University underscores the importance of implementing a multifaceted approach to understanding tumor biology and the tumor ecosystem as a way to promote better clinical outcomes in ccRCC patients,” said Nathan Fowler, MD, Chief Medical Officer at BostonGene. “We believe these integrated methods to identify biomarkers of response to therapies will ultimately help to improve precision medicine strategies for these patients.”

“This study was designed to characterize the role of the tumor microenvironment in ccRCC using multiomic analyses,” said James Hsieh, MD, PhD, a medical oncologist and Professor of Medicine at Washington University School of Medicine in St Louis. “The findings indicated tumor behavior specificities linked with patient responses, and the MxIF analyses identified 14 unique cellular neighborhoods in multi-region tumors that can be utilized to optimize treatment strategies for patients with ccRCC.”


Miheecheva N, Postovalova E, Lyu Y, Ramachandran A, Bagaev A, Svekolkin V, Galkin I, Zyrin V, Maximov V, Lozinsky Y, Isaev S, Ovcharov P, Shamsutdinova D, Cheng EH, Nomie K, Brown JH, Tsiper M, Ataullakhanov R, Fowler N, Hsieh JJ. (2022) Multiregional single-cell proteogenomic analysis of ccRCC reveals cytokine drivers of intratumor spatial heterogeneity. Cell Rep 40(7):111180. [article]

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