Endogenous retrovirus expression is associated with response to immune checkpoint blockade in clear cell renal cell carcinoma
Anshuman Panda, Aguirre A. de Cubas, Mark Stein, Gregory Riedlinger, Joshua Kra, Tina Mayer, Christof C. Smith, Benjamin G. Vincent, Jonathan S. Serody, Kathryn E. Beckermann, Shridar Ganesan, Gyan Bhanot, W. Kimryn Rathmell
Anshuman Panda, Aguirre A. de Cubas, Mark Stein, Gregory Riedlinger, Joshua Kra, Tina Mayer, Christof C. Smith, Benjamin G. Vincent, Jonathan S. Serody, Kathryn E. Beckermann, Shridar Ganesan, Gyan Bhanot, W. Kimryn Rathmell
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Research Article Immunology Oncology

Endogenous retrovirus expression is associated with response to immune checkpoint blockade in clear cell renal cell carcinoma

Abstract

Although a subset of clear cell renal cell carcinoma (ccRCC) patients respond to immune checkpoint blockade (ICB), predictors of response remain uncertain. We investigated whether abnormal expression of endogenous retroviruses (ERVs) in tumors is associated with local immune checkpoint activation (ICA) and response to ICB. Twenty potentially immunogenic ERVs (πERVs) were identified in ccRCC in The Cancer Genome Atlas data set, and tumors were stratified into 3 groups based on their expression levels. πERV-high ccRCC tumors showed increased immune infiltration, checkpoint pathway upregulation, and higher CD8+ T cell fraction in infiltrating leukocytes compared with πERV-low ccRCC tumors. Similar results were observed in ER+/HER2− breast, colon, and head and neck squamous cell cancers. ERV expression correlated with expression of genes associated with histone methylation and chromatin regulation, and πERV-high ccRCC was enriched in BAP1 mutant tumors. ERV3-2 expression correlated with ICA in 11 solid cancers, including the 4 named above. In a small retrospective cohort of 24 metastatic ccRCC patients treated with single-agent PD-1/PD-L1 blockade, ERV3-2 expression in tumors was significantly higher in responders compared with nonresponders. Thus, abnormal expression of πERVs is associated with ICA in several solid cancers, including ccRCC, and ERV3-2 expression is associated with response to ICB in ccRCC.

Authors

Anshuman Panda, Aguirre A. de Cubas, Mark Stein, Gregory Riedlinger, Joshua Kra, Tina Mayer, Christof C. Smith, Benjamin G. Vincent, Jonathan S. Serody, Kathryn E. Beckermann, Shridar Ganesan, Gyan Bhanot, W. Kimryn Rathmell

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Figure 2

Expression of πERVs defines subtypes with differential immune checkpoint activation in ccRCC (KIRC).

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Expression of πERVs defines subtypes with differential immune checkpoint...
(A) Hierarchical clustering of tumors from TCGA (columns) by expression (percentile) of πERVs (rows) stratifies tumors into 3 subtypes (high [H], intermediate [I], and low [L]). (B) Frequency of VHL, PBRM1, SETD2, and BAP1 mutations (dark, truncating mutations; light, other nonsynonymous mutations) in the 3 subtypes. Comparison of (C) overall immune infiltration in tumors (“ImmuneScore”) and fractional composition of tumor-infiltrating leukocytes and (D) mRNA expression of CD8A (cytotoxic T cell marker) and immune checkpoint genes between πERV-high and πERV-low subtypes. Number of samples: (C) ImmuneScore (119 H, 228 L), all other categories (90 H, 134 L), (D) 119 H and 228 L. P values reported in bar plots and box plots are from Fisher’s exact test and Wilcoxon rank-sum test, respectively (all 2 sided). *P < 0.05, **P < 10–3, ***P < 10–6.