Human kallikrein 4 signal peptide induces cytotoxic T cell responses in healthy donors and prostate cancer patients

Abstract

Immunotherapy is a promising new treatment for patients with advanced prostate and ovarian cancer but its application is limited by the lack of suitable target antigens that are recognized by CD8 + cytotoxic T lymphocytes (CTL). Human kallikrein 4 (KLK4) is a member of the kallikrein family of serine proteases that is significantly over-expressed in malignant versus healthy prostate and ovarian tissue, making it an attractive target for immunotherapy. We identified a naturally processed, HLA-A*0201-restricted peptide epitope within the signal sequence region of KLK4 that induced potent CTL responses in vitro in most healthy donors and prostate cancer patients tested. These CTL lysed HLA-A*0201 + prostate and ovarian cancer cell lines expressing KLK4. CTL specific for the HLA-A*0201-restricted KLK4 peptide were more readily expanded to a higher frequency in vitro compared to the known HLA-A*0201-restricted epitopes from prostate cancer antigens; prostate specific antigen (PSA), prostate specific membrane antigen (PSMA) and prostatic acid phosphatase (PAP). These data demonstrate that KLK4 is an immunogenic molecule capable of inducing CTL responses and identify it as an attractive target for prostate and ovarian cancer immunotherapy.

Phase I/II study exploring ImMucin, a pan‐major histocompatibility complex, anti‐MUC1 signal peptide vaccine, in multiple myeloma patients

“…We can ascribe this strong and broad immune response to the lipophilic sequences within SP domains, such as MUC1‐SP‐L, which has been shown by us (Kovjazin et al , ,b, ; Kovjazin & Carmon, ) and others (Wilkinson et al , ; Kerzerho et al , ) to be more immunogenic than other protein domains, and which, in the case of ImMucin, can generate a rapid response, using a low dose of naked LP administered in conjunction with hGM‐CSF, without employing a dedicated ‘carrier system’ or specific adjuvants. In contrast, other anti‐MUC1 vaccination strategies primarily induce humoral responses and/or selected CD8+ T‐cell activation in a subset of patients (Roulois et al , ).…”

The use of signal peptide domains as vaccine candidates

“…10,11 More recently, it has become evident, that apart from the consensus motif essential for the role of the SP as a targeting signal, SP domains exhibit high antigenic variability and specificity to the proteins they derived from, 8,[12][13][14] enabling them to serve as VCs. Yet, while select MHC class I, [15][16][17] class II 6,18-20 and HLA-E 21,22 single epitopes have already been identified in different SP domains, and shown to specifically activate T-cells, and more rarely inhibit select NK-cells, the broader potential of using the entire SP domains as multi-epitope long peptides (LP) and their ability to induce robust antigenspecific T and B-cell response has not been explored.…”

Genetic Association of the KLK4 Locus with Risk of Prostate Cancer

“…It is unknown what the potential functional effects of an amino acid substitution are within the signal peptide. However, a recent study has shown that this cleaved peptide may be a useful target in prostate cancer immunotherapy, with the KLK4 signal peptide successfully inducing and expanding the cytotoxic T lymphocyte response more readily than PSA or Prostatic Acid Phosphotase (PAP) [42]. In addition, in silico analysis using the signal peptide prediction program SignalP [43] predicted a Serine22Alanine substitution to alter the cleavage site from aa 26/27 to aa 21/22.…”