Indeed, when MHC-I neoepitopes are targeted with long epitope immunogens, off-target binding to MHC-II occurs, resulting in indirect CD4 + T-cell responses that drive antitumor immunity. As a result of these challenges, namely, predicting which neoepitopes are immunogenic and which give rise to functional CD8 + T-cell responses, multivalent immunization strategies are common, with the intent that even a single epitope from a neoepitope cocktail would elicit therapeutic efficacy.Р”В®ven though short, synthetic MHC-I epitopes are low-cost, contain the required biochemical information to induce Ag-specific CD8 + T cells, and represent the most rational target for injectable neoepitope vaccines, virtually all recent clinical 12РІР‚вЂњ15 and preclinical 16РІР‚вЂњ19 neoepitope discoveries make use of long epitope immunogens (typically 25РІР‚вЂњ100 amino acids) that are less relevant for direct or efficient binding to the MHC-I molecule. 11 However, induction alone is not sufficient for cancer therapy since, in addition, those epitopes need to be displayed in sufficient quantity in the context of the appropriate MHC-I of the tumor target. Exploratory clinical trials with dendritic cell vaccines using a small cocktail of short peptide neoepitopes have shown that neoepitope-specific CD8 + T cells can be induced in humans. 9 However, since patients rarely share neoepitopes, 10 understanding which ones represent functional immunogenic targets has been challenging. In theory, these bypass challenges related to central immune tolerance, and mutations from primary tumors (that would be analyzed to identify neoepitopes) are maintained during disseminated disease. 5РІР‚вЂњ8 CD8 + T-cell neoepitopes include tumor-specific, mutated MHC-I binding epitopes and represent a rich source of personalized cancer vaccine targets. 4 These short peptides are 8РІР‚вЂњ10 amino acids in length and need to be expressed, bound, and processed from their parent proteins to be displayed on MHC-I surfaces of antigen-presenting cells (APCs) or target cells, where they would be engaged by a CD8 + T cell expressing an appropriate TCR for that neoepitope. The development of tools for evaluating new immunotherapies based on induction of CD8 + cytotoxic T lymphocytes, specifically those that can recognize tumor-specific Ags such as neoepitopes, could be useful to accelerate RCC research.Р”В¬D8 + T-cell responses form the backbone of cancer immunotherapy and are initiated and executed by forming the peptideРІР‚вЂњmajor histocompatibility class I (MHC-I) T-cell receptor (TCR) complex. 3 Within preclinical research, the mouse renal adenocarcinoma RENCA model is a commonly used tumor model to assess RCC immunotherapies. 2 A tumor-associated antigen (Ag) peptide vaccine, IMA901, was assessed in phase III clinical trials but did not improve patient outcomes. 1 Likely due to its immunogenicity, RCC has been a prime target for cancer immunotherapies, initially with high-dose interleukin (IL)-2 approved by the US Food and Drug Administration in 1992 and, more recently, with programmed cell death protein 1 (PD-1) antibody immune checkpoint blockade (ICB) approved in 2015, followed by cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and programmed death-ligand 1 antibody ICB.

Renal cell carcinoma (RCC) is among the 10 most common cancers globally, with an incidence rising in the past decade.

Correspondence to Dr Jonathan F Lovell, Department of Biomedical Engineering, University at Buffalo, State University of New York, Buffalo, NY, 14260, USA.

7 Department of Immunology, Roswell Park Comprehensive Cancer Center, Buffalo, New York, USA.

6 Department of Medicine, State University of New York, Buffalo, NY, USA.5 Department of Medicine, Columbia University Irving Medical Center, New York, NY, USA.4 Department of Anatomy and Cell Biology, McGill University, Montreal, QuР“В©bec, Canada.3 Center for Computational Research, University at Buffalo, Buffalo, NY, USA.2 Department of Experimental Therapeutics, Roswell Park Comprehensive Cancer Center, Buffalo, New York, USA.1 Department of Biomedical Engineering, University at Buffalo, Buffalo, New York, USA.

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