Uncovering the Tumor Antigen Landscape: What to Know about the Discovery Process

Abstract

According to the latest available data, cancer is the second leading cause of death, highlighting the need for novel cancer therapeutic approaches. In this context, immunotherapy is emerging as a reliable first-line treatment for many cancers, particularly metastatic melanoma. Indeed, cancer immunotherapy has attracted great interest following the recent clinical approval of antibodies targeting immune checkpoint molecules, such as PD-1, PD-L1, and CTLA-4, that release the brakes of the immune system, thus reviving a field otherwise poorly explored. Cancer immunotherapy mainly relies on the generation and stimulation of cytotoxic CD8 T lymphocytes (CTLs) within the tumor microenvironment (TME), priming T cells and establishing efficient and durable anti-tumor immunity. Therefore, there is a clear need to define and identify immunogenic T cell epitopes to use in therapeutic cancer vaccines. Naturally presented antigens in the human leucocyte antigen-1 (HLA-I) complex on the tumor surface are the main protagonists in evocating a specific anti-tumor CD8+ T cell response. However, the methodologies for their identification have been a major bottleneck for their reliable characterization. Consequently, the field of antigen discovery has yet to improve. The current review is intended to define what are today known as tumor antigens, with a main focus on CTL antigenic peptides. We also review the techniques developed and employed to date for antigen discovery, exploring both the direct elution of HLA-I peptides and the in silico prediction of epitopes. Finally, the last part of the review analyses the future challenges and direction of the antigen discovery field.

Blood donor biobank and HLA imputation as a resource of HLA homozygous cells for therapeutic and research use

“…Firstly, as suggested by Taylor et al [8] and Nakatsuji et al [9] and others, the HLA homozygotes are a good source for HLA compatible embryonic stem cells and iPS cells. Several estimates of population coverage at various HLA matching levels in diverse populations have been reported [18, [34][35][36][37]. It has been estimated, that approximately 20,000 HLA homozygotes would be needed to reach ~ 50% coverage in European populations [28].…”

A novel immunopeptidomic-based pipeline for the generation of personalized oncolytic cancer vaccines

“…We decided to identify and isolate peptides directly from the MHC-I complexes, exploiting state-of-the-art immunoprecipitation and mass spectrometric methodologies as the direct elution and analysis of MHC-I restricted peptides is so far the most reliable and used approach in studies of ligandome landscape (2), identifying naturally processed and presented tumor epitopes that could generate clinically relevant anti-tumor responses. Even tough computational algorithms can take into account the entire MHC complex presentation machinery (e.g., proteasomal cleavage, transporter-associated antigen processing (TAP) transport, binding motif) to predict relevant T cell epitopes, the lack of validated and homogenous datasets makes the process difficult and less reproducible (22,23). These considerations prompted us to adopt direct MHC-I immunoaffinity purification as first step of our pipeline.…”

The Role of Antigen Processing and Presentation in Cancer and the Efficacy of Immune Checkpoint Inhibitor Immunotherapy

“…Several research efforts have already aimed at the identification of naturally presented antigens in different types of hematological and solid tumors while new tools and techniques (i.e., mass spectrometry-based and in silico, proteogenomic techniques etc.) are being developed and integrated, aiming for a more precise characterization and validation of the cancer-specific immunopeptidomes [ 181 , 182 , 183 , 184 , 185 , 186 , 187 , 188 ].…”