New data suggest that expression of transcriptionally active human endogenous retroviruses (hERVs) is associated with prognosis in clear cell renal cell carcinoma (ccRCC) and that hERV signatures associated with specific immune mechanisms could predict patient survival.

“Unlike other immunotherapy-sensitive tumours, ccRCC is not characterized by a high mutation burden, despite a high response rate to immunotherapy,” explains lead author Ben Vincent. “This led us to the hypothesis that other factors in ccRCC, including hERV expression, could alter the tumour microenvironment and affect response to immunotherapy.”

Vincent’s team designed a computational workflow (hervQuant) for identifying hERV expression from The Cancer Genome Atlas (TCGA). Different cancers displayed similar hERV expression patterns; however, testicular germ cell tumour and uveal melanoma, which arise from immune-privileged tissues, had less similar profiles, suggesting that the shared hERV expression profiles in other tumour types might have been affected by tumour immune responses.

Multivariable linear regression of hERV expression by cancer type examined the association between hERV expression and immune features, age, and overall survival (OS). Significant hERVs included those associated with immune cells known to have antitumour functions, including effector and central memory T cells and natural killer (NK) cells. Furthermore, a signature of anti-programmed cell death 1 (PD-1) was positively associated with hERV expression, and a signature for anti-PD-1 in nonresponder tumour biopsies was negatively associated with all hERV expression. Cox regression of hERV expression and clinical outcome showed that patients with greater mean hERV expression had worse outcomes in all cancers except bladder cancer. Of all the cancer types included in TCGA, ccRCC contained the greatest number of prognostic hERVs. Thus, the role of hERVs in ccRCC was further examined, focusing on two mechanisms by which hERV expression could influence the tumour immune microenvironment: activation of retinoic acid-inducible gene I (RIG-I)-like pathway signalling and hERV epitope-triggered T cell and B cell activation.

Study of the association between hERV expression and genes in the RIG-I-like receptor signature led to the identification of two biologically distinct hERV groups. Both groups showed positive associations between hERV expression and agonistic genes to the RIG-I-like pathway, but group 2 hERVs were also positively associated with key antagonist genes in the nuclear factor-κB (NF-κB) pathway and negatively associated with NF-κB agonistic genes. Regression analysis of hERV expression in the ccRCC TCGA cohort showed that the majority of group 1 hERVs were associated with longer OS, whereas group 2 hERVS were associated with shorter OS. In addition, presence of B cell receptors was associated with hERV expression, suggesting a hERV-epitope-driven B cell response.

The hERV identified as the most differentially expressed with greatest evidence of translation (hERV 4700) was tested for predictive ability of patient response to anti-PD-1 therapy. The hERV 4700 reverse transcription quantitative PCR signal and hervQuant-derived hERV 4700 expression were both greater in anti-PD-1 responders than nonresponders, indicating that hERV 4700 transcription could be associated with increased responsiveness to immunotherapy.

patients with greater mean hERV expression had worse outcomes

In their discussion, the authors assert that “hERVs may either directly interact with antitumour immunity through immune activation or provide a biomarker for an active antitumour immune response.”