Preprocalcitonin signal peptide generates a cytotoxic T lymphocyte-defined tumor epitope processed by a proteasome-independent pathway

Hage, Faten El; Stroobant, Vincent; Vergnon, Isabelle; Baurain, Jean‐François; Echchakir, Hamid; Lazar, Vladimir; Chouaı̈b, Salem; Coulie, Pierre G.; Mami‐Chouaib, Fathia

doi:10.1073/pnas.0802753105

Cited by 69 publications

(86 citation statements)

References 42 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…ϩ T cell epitopes resides in the signal peptide, as described previously for other secreted tumor antigens (17)(18)(19). These findings suggest that MDK may be novel candidate for the development of a cancer vaccine.…”

Section: Midkine (Mdk)mentioning

confidence: 69%

See 1 more Smart Citation

The Signal Peptide of the Tumor-shared Antigen Midkine Hosts CD4+ T Cell Epitopes

Kerzerho¹,

Schneider²,

Favry³

et al. 2013

Journal of Biological Chemistry

View full text Add to dashboard Cite

Background: The CD4 T cell response to the tumor antigen Midkine was unknown. Results: Most of the T cell response to Midkine relies on T cell epitopes contained in its signal peptide. Conclusion:The signal peptide of Midkine is accessible to HLA class II pathway for CD4 T cell presentation. Significance: It is a new function for signal peptides to contribute to tumor-specific CD4 T cell response.

show abstract

Section: Midkine (Mdk)mentioning

confidence: 69%

“…ϩ T cell epitopes, as has been found for numerous tumor and viral antigens (17)(18)(19). Again, the presence of several hydrophobic residues in signal peptides favors their binding to HLA-A2 (33).…”

Section: Discussionmentioning

confidence: 93%

The Signal Peptide of the Tumor-shared Antigen Midkine Hosts CD4+ T Cell Epitopes

Kerzerho¹,

Schneider²,

Favry³

et al. 2013

Journal of Biological Chemistry

View full text Add to dashboard Cite

show abstract

“…In a parallel study, a proteasome-and TAPindependent tumor antigen from the signal sequence of the preprocalcitonin protein (ppCT [16][17][18][19][20][21][22][23][24][25] ) was found to represent a human TEIPP, in that this HLA-A2 presented peptide was selectively presented by tumor cells with TAP deficiency [54]. This peptide is liberated in the ER lumen by sequential cleavage with SP and SPP [55] and is a clear example of the alternative TAP-independent peptide repertoire.We emphasize that not all TAP-independent peptides fail to be presented by processing intact cells. Mass spectrometry analyses have revealed that part of this repertoire can be detected on the surface of TAP-proficient cells [25][26][27].…”

mentioning

confidence: 99%

Peptide transporter TAP mediates between competing antigen sources generating distinct surface MHC class I peptide repertoires

et al. 2011

View full text Add to dashboard Cite

We recently described a category of TAP-independent peptide-epitopes that are selectively presented by cells with processing defects in the classical MHC class I (MHC-I) pathway. Here, we studied the ER-resident ceramide synthase Trh4 as a prototypic example of these neo-antigens and found that moderate inhibition of TAP permits cell surface presentation of the Trh4 peptide. The absence of this peptide from WT cells was not related to the binding or stability of the Trh4/D b complexes, or to the availability of MHC-I heavy chains, but rather to the limited expression of the antigen. Strongly elevated antigen levels were needed to reach comparable peptide display on WT as on TAP-deficient cells. Our data suggest that the normal influx of TAP-transported peptides in the ER during routine processing creates an efficient barrier for peptides from alternative processing routes. Impairment of TAP function, as commonly found in cancers and virus-infected cells, lowers this resistance allowing for MHC-I presentation of other peptide sources.Key words: Antigen processing . Cytotoxic T lymphocytes . Transporter associated with peptide processing Supporting Information available online IntroductionCytotoxic T lymphocytes (CTLs) are key effector cells of the adaptive immune system and circulate throughout the body in search of their cognate peptides that are presented by MHC class I (MHC-I) molecules. T-cell receptors determine the antigen specificity of CTLs and engagement with peptide/MHC-I complexes leads to their activation and elimination of target cells. Therefore, the process of MHC-I antigen processing and presentation, which operates in all nucleated cells of our body, is crucial for CTL immune surveillance [1][2][3]. The highly complex repertoire of MHC-I presented peptides reflects the total proteome of cells and derives from the physiological turnover of proteins, a process that is largely operated by the multicatalytic enzyme proteasome [4,5]. In addition to the proteasome, other proteolytic enzymes in the cytosol have been implicated in the liberation of peptides for MHC-I presentation, some of which can compensate for the lack of proteasome activity [1,6,7]. For instance, tripeptidyl peptidase II (TPPII), insulin-degrading enzyme (IDE), thimet oligopeptidase (TOP) and nardilysin have been implicated in the generation of some CTL epitopes [8][9][10]. However, the relative contributions of these novel peptidases and Ã These authors contributed equally to this work 3114their cooperation with the proteasome have not been fully characterized.The intermediate peptide products are rescued from total breakdown by these cytosolic proteases through translocation into the ER. Subsequently, peptides are trimmed and loaded into the grooves of MHC-I molecules, a dynamic process that is mediated by the peptide loading complex (PLC) consisting of MHC-I, b2m, ERp57, TAP, tapasin and chaperones [11][12][13]. The TAP peptide transport is operated by the heterodimer pump TAP1/TAP2, members of the ABC transporter family. The imp...

show abstract

“…Our data provides one example since we were able to more readily detect and expand CTL specific for the KLK4A epitope compared to other HLA-A*0201-restricted peptides such as PSA 154-163 , PAP 299-307 and KLK4B,D,E that are located in their respective core proteins. In support of this theory, HLA-A*0201-restricted immunogenic epitopes have been identified within the signal peptides of other human TAA, including the melanoma antigen tyrosinase [32][33] and the medullary thyroid and lung carcinoma associated CALCA gene [31]. Notably, a HLA-A*0201-restricted epitope is located within the signal sequence of MUC1…”

Section: Discussionmentioning

confidence: 68%

“…The location of the epitope within the signal sequence may explain why KLK4A-specific CTL responses were readily induced in both healthy donors and prostate cancer patients. Signal peptide molecules are known to associate with HLA-A*0201 molecules [29][30] and their capacity to induce CTL has been documented in a few cases [31][32][33][34][39][40]. Epitopes derived from signal peptides can be directly processed and presented on MHC Class I when expressed endogenously by tumor cells or DC (direct presentation) [40].…”

Section: Discussionmentioning

confidence: 99%

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

Wilkinson

Woods

D’Rozario

et al. 2011

Cancer Immunol Immunother

View full text Add to dashboard Cite

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.

show abstract

Preprocalcitonin signal peptide generates a cytotoxic T lymphocyte-defined tumor epitope processed by a proteasome-independent pathway

Cited by 69 publications

References 42 publications

The Signal Peptide of the Tumor-shared Antigen Midkine Hosts CD4+ T Cell Epitopes

The Signal Peptide of the Tumor-shared Antigen Midkine Hosts CD4+ T Cell Epitopes

Peptide transporter TAP mediates between competing antigen sources generating distinct surface MHC class I peptide repertoires

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

Contact Info

Product

Resources

About