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Higher human lymphocyte antigen class I expression in early-stage cancer cells leads to high sensitivity for cytotoxic T lymphocytes.

ABSTRACT: Human lymphocyte antigen (HLA) class I molecules play a central role in cytotoxic T lymphocytes (CTL)-based antitumor immunity. However, the expression rate of HLA class I in cancer cells remains a topic of discussion. We compared HLA class I expression levels between cancer cells and surrounding non-tumorous hepatocytes in 20 early-stage hepatocellular carcinoma (HCC) patients by immunohistochemistry using EMR 8-5. The expression levels of HLA class I were classified as negative, incomplete positive or complete positive. Similarly, for various types of solid cancers, HLA class I expression was examined. For the HLA class I expression in cancer cells, among 20 HCC patients, 13 were complete positive, 3 were incomplete positive, and 4 were negative. In addition, 15 (75.0%) had higher expression levels of HLA class I in cancer cells compared with that in surrounding non-tumorous hepatocytes. An interferon-γ (IFN-γ) enzyme-linked immunospot (ELISPOT) assay indicated that cancer cells with positive expression of HLA class I had strong sensitivity to antigen-specific CTL. We suggested that HLA class I expression in cancer cells could be involved in the clinical prognosis of HCC patients. Similarly, 66.7%, 100.0%, 66.7% and 62.5% of patients with early-stage pancreatic, gallbladder, esophageal and breast cancers, respectively, had higher expression levels of HLA class I in cancer cells than in surrounding normal tissue cells. We suggest that in several early-stage solid cancers, including HCC, HLA class I expression levels in cancer cells are higher than that in surrounding normal tissue cells, which could result in the anti-tumor effect of CTL-based cancer immunotherapy.

SUBMITTER: Akazawa Y

PROVIDER: S-EPMC6549930 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Purpose Peripheral blood-derived antigen-specific cytotoxic T cells (CTLs) provide a readily available source of effector cells that can be administered with minimal toxicity in an outpatient setting. In metastatic melanoma, this approach results in measurable albeit modest clinical responses in patients resistant to conventional therapy. We reasoned that concurrent cytotoxic T-cell lymphocyte antigen-4 (CTLA-4) checkpoint blockade might enhance the antitumor activity of adoptively transferred CTLs. Patients and Methods Autologous MART1-specific CTLs were generated by priming with peptide-pulsed dendritic cells in the presence of interleukin-21 and enriched by peptide-major histocompatibility complex multimer-guided cell sorting. This expeditiously yielded polyclonal CTL lines uniformly expressing markers associated with an enhanced survival potential. In this first-in-human strategy, 10 patients with stage IV melanoma received the MART1-specific CTLs followed by a standard course of anti-CTLA-4 (ipilimumab). Results The toxicity profile of the combined treatment was comparable to that of ipilimumab monotherapy. Evaluation of best responses at 12 weeks yielded two continuous complete remissions, one partial response (PR) using RECIST criteria (two PRs using immune-related response criteria), and three instances of stable disease. Infused CTLs persisted with frequencies up to 2.9% of CD8+ T cells for as long as the patients were monitored (up to 40 weeks). In patients who experienced complete remissions, PRs, or stable disease, the persisting CTLs acquired phenotypic and functional characteristics of long-lived memory cells. Moreover, these patients also developed responses to nontargeted tumor antigens (epitope spreading). Conclusion We demonstrate that combining antigen-specific CTLs with CTLA-4 blockade is safe and produces durable clinical responses, likely reflecting both enhanced activity of transferred cells and improved recruitment of new responses, highlighting the promise of this strategy.

Project description:The identification of novel biomarkers and therapeutic targets in advanced cancer is critical for improving cancer diagnosis and therapeutics. Survivin (SV) is highly expressed predominantly in most cancer cells and tissues but is absent or undetectable in terminally differentiated normal adult tissues. Therefore, it functions as an almost universal tumor antigen. Peptides are short chains of amino acids linked by peptide bonds. To obtain novel SV decamers that are able to induce SV-specific cytotoxic T lymphocytes (CTLs) with a higher cytotoxic efficiency against cancer cells, major histocompatibility complex (MHC) peptide binding algorithms were conducted to predict nine modified SV95 decamers (from SV95-2 to SV95-10) based on the natural SV95-104 peptide sequence of ELTLGEFLKL (here defined as SV95-1). The fluorescent density of each SV95 peptide was determined by a MHC stability assay, followed by the generation of SV95-specific CTLs with each SV95 peptide (from SV95-1 to SV95-10) and human dendritic cells (DCs) loaded with Poly(lactic-co-glycolic) acid (PLGA) nanoparticles encapsulated with SV95 peptide. Finally, IFN-γ ELISpot and CytoTox 96® Non-Radioactive Cytotoxicity Assays were employed to verify their cytotoxic efficiency of the SV95-specific CTLs generated with the corresponding artificial antigen presenting cells (aAPCs) containing SV95 (SV95-1 to SV95-10) peptide. Furthermore, the cytotoxicity of the SV95 specific CTLs generated with nine mutated SV95 peptides was compared to the one generated with natural SV95-1 peptide and TIL2080 cells. The results indicated that the HLA-A2-restricted mutated SV95 epitope decamers (SV95-6 and SV95-7) showed significant higher binding ability compared to natural peptide SV95-1 in MHC stability assay. More importantly, SV95-specific CTLs with higher cytotoxicity were successfully induced with both SV95-6 and SV95-7 peptides, which significantly eliminated target cells (not only SV95-1 peptide pulsed T2 cells, but also both HLA-A2 and SV positive cancer cells) when compared to those generated with natural SV95-1 peptide and TIL2080 cells. These findings suggest that the SV95-6 and SV95-7 peptides are two novel HLA-A2-restricted CTL epitopes and may be useful for the immunotherapy for patients with survivin expressing cancer.

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Higher human lymphocyte antigen class I expression in early-stage cancer cells leads to high sensitivity for cytotoxic T lymphocytes.

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