Complement as prognostic biomarker and potential therapeutic target in renal cell carcinoma

Britney Reese, Ashok Silwal, Elizabeth Daugherity, Michael Daugherity, Mahshid Arabi, Pierce Daly, Yvonne Paterson, Layton Woolford, Alana Christie, Roy Elias, James Brugarolas, Tao Wang, Magdalena Karbowniczek, Maciej M. Markiewski

Research output: Contribution to journalArticlepeer-review

2 Scopus citations

Abstract

Preclinical studies demonstrated that complement promotes tumor growth. Therefore, we sought to determine the best target for complement-based therapy among common human malignancies. High expression of 11 complement genes was linked to unfavorable prognosis in renal cell carcinoma. Complement protein expression or deposition was observed mainly in stroma, leukocytes, and tumor vasculature, corresponding to a role of complement in regulating the tumor microenvironment. Complement abundance in tumors correlated with a high nuclear grade. Complement genes clustered within an aggressive inflammatory subtype of renal cancer characterized by poor prognosis, markers of T cell dysfunction, and alternatively activated macrophages. Plasma levels of complement proteins correlated with response to immune checkpoint inhibitors. Corroborating human data, complement deficiencies and blockade reduced tumor growth by enhancing antitumor immunity and seemingly reducing angiogenesis in a mouse model of kidney cancer resistant to PD-1 blockade. Overall, this study implicates complement in the immune landscape of renal cell carcinoma, and notwithstanding cohort size and preclinical model limitations, the data suggest that tumors resistant to immune checkpoint inhibitors might be suitable targets for complement-based therapy.

Original languageEnglish (US)
Pages (from-to)3218-3229
Number of pages12
JournalJournal of Immunology
Volume205
Issue number11
DOIs
StatePublished - Dec 1 2020

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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