Autophagosome-based strategy to monitor apparent tumor-specific CD8 T cells in patients with prostate cancer

Abstract

The immune system plays an essential role in eradicating cancer in concert with various treatment modalities. In the absence of autologous tumor material, no standardized method exists to assess T cell responses against the many antigens that may serve as cancer rejection antigens. Thus, development of methods to screen for therapy-induced anti-tumor responses is a high priority that could help tailor therapy. Here we tested whether a tumor-derived antigen source called DRibbles®, which contain a pool of defective ribosomal products (DRiPs), long-lived and short-lived proteins (SLiPs) and danger-associated molecular patterns (DAMPs), can be used to identify tumor-associated antigen (TAA)-specific responses in patients before or after immunotherapy treatment. Protein content, gene expression and non-synonymous – single nucleotide variants (ns-SNVs) present in UbiLT3 DRibbles were compared with prostate adenocarcinomas and the prostate GVAX vaccine cell lines (PC3/LNCaP). UbiLT3 DRibbles were found to share proteins, as well as match tumor sequences for ns-SNVs with prostate adenocarcinomas and with the cell lines PC3 and LNCaP. UbiLT3 DRibbles were used to monitor anti-tumor responses in patients vaccinated with allogeneic prostate GVAX. UbiLT3-DRibble-reactive CD8+ T-cell responses were detected in post-vaccine PBMC of 6/12 patients (range 0.85–22% of CD8+ cells) after 1 week in vitro stimulation (p = 0.007 vs. pre-vaccine). In conclusion, a cancer-derived autophagosome-enriched preparation, packaging over 100 proteins over-expressed in prostate cancer into microvesicles containing DAMPs, could be used to identify CD8+ T cells in peripheral blood from patients after prostate GVAX vaccination and may represent a general method to monitor anti-cancer T cell responses following immunotherapy.

A Local and Low-Dose Chemotherapy/Autophagy-Enhancing Regimen Treatment Markedly Inhibited the Growth of Established Solid Tumors Through a Systemic Antitumor Immune Response

“…The level of autophagy in cancer cells affects the release of several cytokines and danger signals that instruct immune effectors to induce immune responses (17)(18)(19). When autophagy is hyperactivated, tumor-derived cytoplasmic components are made available for lysosomal hydrolysis, thereby promoting antigen processing in dying tumor cells (20,21). Additionally, highly activated autophagy can increase the secretion of adenosine triphosphate (ATP) by dying tumor cells, and ATP acts as a vital signal for the activation of dendritic cells (DCs) and cytotoxic T cells and their recruitment into the local tumor microenvironment (22,23).…”

Emerging potential of immunopeptidomics by mass spectrometry in cancer immunotherapy

“…[5][6][7][8] Furthermore, the development of cancer vaccines has also been considered to be a major challenge in cancer immunology to prevent and fight against cancer. [9][10][11][12][13] In order to obtain a potential therapeutic cancer antigen from thousands of immunopeptide sequences, previous research has relied on a prediction system which usually provides dozens to hundreds of candidate sequences for further screening steps. The presentation machinery of class I immunopeptides is highly complex, involving genetic alteration, source translation, and the cancer microenvironment (Figure 2).…”