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Publications

Journal Article Epublish 14 citations

PubMed: 39639369 DOI: 10.1186/s13059-024-03435-z

Increased spatial coupling of integrin and collagen IV in the immunoresistant clear-cell renal-cell carcinoma tumor microenvironment.

Genome Biol 25(1):308

Authors: Alex C Soupir, Mitchell T Hayes, Taylor C Peak, Oscar Ospina, Nicholas H Chakiryan, Anders E Berglund, Paul A Stewart, Jonathan Nguyen, Carlos Moran Segura, Natasha L Francis, Paola M Ramos Echevarria, Jad Chahoud, Roger Li, Kenneth Y Tsai, Jodi A Balasi, Yamila Caraballo Peres, Jasreman Dhillon, Lindsey A Martinez, Warren E Gloria, Nathan Schurman, Sean Kim, Mark Gregory, James Mulé, Brooke L Fridley, Brandon J Manley

Affiliations

  • Department of Biostatistics and Bioinformatics, Moffitt Cancer Center, Tampa, FL, 33612, USA.
  • Department of Genitourinary Oncology, Moffitt Cancer Center, Tampa, FL, 33612, USA.
  • Department of Urology, Oregon Health & Science University, Portland, OR, 97239, USA.
  • Department of Pathology, Moffitt Cancer Center, Tampa, FL, 33612, USA.
  • Tissue Core, Moffitt Cancer Center, Tampa, FL, 33612, USA.
  • Nontherapeutic Research Operations, Moffitt Cancer Center, Tampa, FL, 33612, USA.
  • NanoString, Seattle, WA, 98109, USA.
  • Department of Immunology, Moffitt Cancer Center, Tampa, FL, 33612, USA.
  • Division of Health Services and Outcomes Research, Children's Mercy Hospital, Kansas, MO, USA.
  • Department of Genitourinary Oncology, Moffitt Cancer Center, Tampa, FL, 33612, USA.

Abstract

BACKGROUND

Immunotherapy has improved survival for patients with advanced clear cell renal cell carcinoma (ccRCC), but resistance to therapy develops in most patients. We use cellular-resolution spatial transcriptomics in patients with immunotherapy naïve and exposed primary ccRCC tumors to better understand immunotherapy resistance.

RESULTS

Spatial molecular imaging of tumor and adjacent stroma samples from 21 tumors suggests that viable tumors following immunotherapy harbor more stromal CD8 + T cells and neutrophils than immunotherapy naïve tumors. YES1 is significantly upregulated in immunotherapy exposed tumor cells. Spatial GSEA shows that the epithelial-mesenchymal transition pathway is spatially enriched and the associated ligand-receptor transcript pair COL4A1-ITGAV has significantly higher autocorrelation in the stroma after exposure to immunotherapy. More integrin αV + cells are observed in immunotherapy exposed stroma on multiplex immunofluorescence validation. Compared to other cancers in TCGA, ccRCC tumors have the highest expression of both COL4A1 and ITGAV. Assessing bulk RNA expression and proteomic correlates in CPTAC databases reveals that collagen IV protein is more abundant in advanced stages of disease.

CONCLUSIONS

Spatial transcriptomics of samples of 3 patient cohorts with cRCC tumors indicates that COL4A1 and ITGAV are more autocorrelated in immunotherapy-exposed stroma compared to immunotherapy-naïve tumors, with high expression among fibroblasts, tumor cells, and endothelium. Further research is needed to understand changes in the ccRCC tumor immune microenvironment and explore potential therapeutic role of integrin after immunotherapy treatment.

MeSH

Cells, Integrins, Neoplasms, Collagen, Carcinoma, Renal Cell, Immunotherapy, Therapeutics, Tumor Microenvironment

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