Endogenous retroviral signatures predict immunotherapy response in clear cell renal cell carcinoma
Christof C. Smith, … , Sara R. Selitsky, Benjamin G. Vincent
Christof C. Smith, … , Sara R. Selitsky, Benjamin G. Vincent
Published August 23, 2018
Citation Information: J Clin Invest. 2018;128(11):4804-4820. https://doi.org/10.1172/JCI121476.
View: Text | PDF
Research Article Immunology Oncology

Endogenous retroviral signatures predict immunotherapy response in clear cell renal cell carcinoma

Abstract

Human endogenous retroviruses (hERVs) are remnants of exogenous retroviruses that have integrated into the genome throughout evolution. We developed a computational workflow, hervQuant, which identified more than 3,000 transcriptionally active hERVs within The Cancer Genome Atlas (TCGA) pan-cancer RNA-Seq database. hERV expression was associated with clinical prognosis in several tumor types, most significantly clear cell renal cell carcinoma (ccRCC). We explored two mechanisms by which hERV expression may influence the tumor immune microenvironment in ccRCC: (i) RIG-I–like signaling and (ii) retroviral antigen activation of adaptive immunity. We demonstrated the ability of hERV signatures associated with these immune mechanisms to predict patient survival in ccRCC, independent of clinical staging and molecular subtyping. We identified potential tumor-specific hERV epitopes with evidence of translational activity through the use of a ccRCC ribosome profiling (Ribo-Seq) dataset, validated their ability to bind HLA in vitro, and identified the presence of MHC tetramer–positive T cells against predicted epitopes. hERV sequences identified through this screening approach were significantly more highly expressed in ccRCC tumors responsive to treatment with programmed death receptor 1 (PD-1) inhibition. hervQuant provides insights into the role of hERVs within the tumor immune microenvironment, as well as evidence that hERV expression could serve as a biomarker for patient prognosis and response to immunotherapy.

Authors

Christof C. Smith, Kathryn E. Beckermann, Dante S. Bortone, Aguirre A. De Cubas, Lisa M. Bixby, Samuel J. Lee, Anshuman Panda, Shridar Ganesan, Gyan Bhanot, Eric M. Wallen, Matthew I. Milowsky, William Y. Kim, W. Kimryn Rathmell, Ronald Swanstrom, Joel S. Parker, Jonathan S. Serody, Sara R. Selitsky, Benjamin G. Vincent

×

Figure 3

hERVs associated with expression of BCR clonotypes are negatively prognostic in ccRCC.

Options: View larger image (or click on image) Download as PowerPoint
hERVs associated with expression of BCR clonotypes are negatively progno...
(A) Heatmap of association (GLM) between hERV expression and expression of B cell clonotypes, displaying all TCRs and BCRs that demonstrate association (left, FDR-corrected P ≤ 0.05) and a magnified view of the top 4 B cell clones with highest numbers of significantly associated hERVs (right, underscored by black box to the bottom left). FDR-corrected P values represented by intensity of color and direction of coefficient represented by color (red: positive, blue: negative). (B) Multiple sequence alignment of areas of DNA identity in ≥25% of hERVs (all hERVs significantly associated with the top 4 B cell clones) and ≥24 base pairs in length (minimum BCR epitope length). Base pair sequences displayed by color (A: blue; T: red; C: green; G: yellow; gap: gray) and sequence below. y axis order is conserved in all plots. (A and B) Color bars at left show superfamily and canonical clade classification. (C) Hazard ratios among all hERVs significantly associated to the top 4 B cell clones (left) or non-BCR-associated hERVs (right) within TCGA KIRC, with Welch’s t test P value displayed. Data represent median (middle line), with boxes encompassing the 25th to 75th percentile, whiskers encompassing 1.5× the interquartile range from the box, and outliers shown by dots. (D) Waterfall plot displaying the log2 fold change in mean expression of hERVs associated with the top 4 B cell clones in the tumor compared with matched normal tissue. FDR-adjusted P value significance (P ≤ 0.05) from DESeq2 analysis displayed in red (positive fold difference), blue (negative fold difference), and gray (nonsignificant).