Endogenous retrovirus expression is associated with response to immune checkpoint pathway 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.

The antibody‐based delivery of interleukin‐12 to solid tumors boosts NK and CD8+ T cell activity and synergizes with immune checkpoint inhibitors

“…51 Besides virally driven tumors (e.g., MCC and HPV-derived malignancies), 20 potentially immunogenic endogenous retroviruses have recently been reported in clear-cell renal cell carcinoma patients. 52 These findings may explain why renal tumors are immunogenic (i.e., respond well to PD-1 blockade 53,54 or to interleukin-2 55 ), in spite of not having a particularly high mutation prevalence. 56 Interestingly, L19-mIL12 triggered a local intratumoral increase of Tregs in LLC lesions, but not in CT26 tumors.…”

The antibody-based delivery of interleukin-12 to solid tumors boosts NK and CD8+T cell activity and synergizes with immune check-point inhibitors

“…When considering human tumors, Miller et al have reported that polyomavirus-specific T cells may represent up to 21% of the T cell specificities within the tumor mass of Merkel Cell Carcinoma (MCC) 53 . Besides virally-driven tumors (e.g., MCC and HPV-derived malignancies), twenty potentially immunogenic endogenous retroviruses have recently been reported in clear-cell renal cell carcinoma patients 54 . These findings may explain why renal tumors are immunogenic (i.e., respond well to PD-1 blockade 55, 56 or to interleukin-2 57 ), in spite of not having a particularly high mutation prevalence 58 .…”

Biomarkers for Response to Immune Checkpoint Blockade

“…Several studies have suggested that a subset of human tumors have abnormal expression of these repetitive RNAs, including ERVs, which leads to the activation of innate immune signaling and upregulation of immune checkpoint genes (Rooney et al 2015, Smith et al 2018, Solovyov et al 2018, Panda et al 2018a). Our research group and others have recently found that ERV expression is associated with evidence of immune checkpoint gene expression and T cell infiltration in several cancers including ccRCC, a cancer with a significant response to immune checkpoint therapy despite having a relatively low TMB (Panda et al 2018a, Rooney et al 2015, Smith et al 2018). Expression of ERVs was found to correlate well with response to ICB in patients with urothelial cancer and patients with ccRCC (Panda et al 2018a, Solovyov et al 2018.…”