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Simple Summary: HCC is a disease with highly unmet medical needs. Specific target antigens for the development of active (vaccine) and/or passive (adoptive T-cell therapy) cancer immunotherapy strategies are needed. The aim of our study was to exploit the high number of data derived from a public dataset to identify HCC-specific overexpressed proteins, leading to potential epitopes recognized by CD8+ cytotoxic T cells, which may share homology to viral epitopes. Circulating CD8+ T cells were revealed to be targeting both HCC and viral-related epitopes, suggesting the possible use in HCC-specific immunotherapies. Hepatocellular carcinoma (HCC) is the third leading cause of death from cancer globally. Indeed, only a few treatments are available, most of which are effective only for the early stages of the disease. Therefore, there is an urgent needing for potential markers for a specifically targeted therapy. Candidate proteins were selected from datasets of The Human Protein Atlas, in order to identify specific tumor-associated proteins overexpressed in HCC samples associated with poor prognosis. Potential epitopes were predicted from such proteins, and homology with peptides derived from viral proteins was assessed. A multiparametric validation was performed, including recognition by PBMCs from HCC-patients and healthy donors, showing a T-cell cross-reactivity with paired epitopes. These results provide novel HCC-specific tumor-associated antigens (TAAs) for immunotherapeutic anti-HCC strategies potentially able to expand pre-existing virus-specific CD8+ T cells with superior anticancer efficacy. [ABSTRACT FROM AUTHOR]

Simple Summary: Endogenous viruses are "ancient" viruses that have coevolved with their host species for millions of years, developing strategies to maintain an equilibrium state with their host. In particular, human endogenous retroviruses (HERVs) are permanently integrated and make up over 8% of our genome. Recent studies have shown that the equilibrium between these endogenous retroviruses and our cells can be broken in several conditions, including cancer. HERV reactivation in cancer cells may result in (a) the activation of a viral defense response against cancer, (b) the production of viral proteins that can be recognized as targets by our immune system and (c) the expression of viral transcripts that can be used as therapeutic targets or markers for prognosis. Overall, this may positively impact on cancer immunotherapy strategies. Human endogenous retroviruses (HERVs) derive from ancestral exogenous retroviruses whose genetic material has been integrated in our germline DNA. Several lines of evidence indicate that cancer immunotherapy may benefit from HERV reactivation, which can be induced either by drugs or by cellular changes occurring in tumor cells. Indeed, several studies indicate that HERV proviral DNA can be transcribed either to double-stranded RNA (dsRNA) that is sensed as a "danger signal" by pattern recognition receptors (PRRs), leading to a viral mimicry state, or to mRNA that is translated into proteins that may contribute to the landscape of tumor-specific antigens (TSAs). Alternatively, HERV reactivation is associated with the expression of long noncoding RNAs (lncRNAs). In this review, we will highlight recent findings on HERV reactivation in cancer and its implications for cancer immunotherapy. [ABSTRACT FROM AUTHOR]