A*02:01/Human Survivin (LMLGEFLKL)/SurA2.M
– Peptide of survivin
Survivin, also called BIRC5, is a member of the apoptosis inhibitor protein family containing a baculovirus domain. Survivin is overexpressed in most human cancers but rarely express in normal differentiated adult tissues. Survivin protein inhibits caspase activation leading to negative regulation of cell death and promote cell proliferation. Survivin localizes in G2/M phase in cell cycle and interacts with tubulin during mitosis. It has been demonstrated that Survivin expression seems to be regulated by the tumor protein p53. Human Survivin contains HLA-A*02:01 binding motifs.
Applications of A*02:01/Human Survivin (LMLGEFLKL)
A*02:01/Human Survivin (LMLGEFLKL)/SurA2.M is an altered peptide of A*02:01/Human Survivin (LTLGEFLKL) which binds the HLA molecules with higher affinity. A*02:01/Human Survivin (LMLGEFLKL) HLA-A*02:01-restricted can be recognized by cytotoxic T lymphocytes on MHC I. Therefore, A*02:01/Human Survivin (LMLGEFLKL) may serve as a target for therapeutics CTL responses and for anticancer immunotherapeutic strategies. A*02:01/Human Survivin (LMLGEFLKL) is used to stimulate CTL responses in peripheral blood mononuclear cells (PBMCs). Then, ELISPOT assay is used to quantify peptide epitope specificity and IFN-γ releasing effector cells. A*02:01/Human Survivin (LMLGEFLKL) is used in vaccine in metastatic melanoma. It has been demonstrated that LMLGEFLKL-specific T cells could be detected among the PBMCs of vaccinated patients.
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1- Altieri D. C. Nat Rev Cancer. 3(1):46-54 (2003)
Acquisition of the ability to evade cellular suicide, or apoptosis, is one of the master switches that contributes to cellular transformation and, ultimately, to invasive cancer. Much has been learned about the molecular organization of apoptotic pathways and their regulators, but the identification and validation of translational targets for apoptosis-based cancer therapy has posed a great challenge. Survivin is an attractive candidate for cancer therapy, so what is its potential applicability in the clinic?
2- Ambrosini G., Adida C. and Altieri D. C. Nat Med. 3(8):917-921 (1997)
Inhibitors of programmed cell death (apoptosis) aberrantly prolonging cell viability may contribute to cancer by facilitating the insurgence of mutations and by promoting resistance to therapy. Despite the identification of several new apoptosis inhibitors related to bcl-2 or to the baculovirus IAP gene, it is not clear whether apoptosis inhibition plays a general role in neoplasia. Here, we describe a new human gene encoding a structurally unique IAP apoptosis inhibitor, designated survivin. Survivin contains a single baculovirus IAP repeat and lacks a carboxyl-terminal RING finger. Present during fetal development, survivin is undetectable in terminally differentiated adult tissues. However, survivin becomes prominently expressed in transformed cell lines and in all the most common human cancers of lung, colon, pancreas, prostate and breast, in vivo. Survivin is also found in approximately 50% of high-grade non-Hodgkin’s lymphomas (centroblastic, immunoblastic), but not in low-grade lymphomas (lymphocytic). Recombinant expression of survivin counteracts apoptosis of B lymphocyte precursors deprived of interleukin 3 (IL-3). These findings suggest that apoptosis inhibition may be a general feature of neoplasia and identify survivin as a potential new target for apoptosis-based therapy in cancer and lymphoma.
3- Li F., Ambrosini G., Chu E. Y., Plescia J., Tognin S., Marchisio P. C. and Altieri D. C. Nature. 396(6711):580-584 (1998)
Progression of the cell cycle and control of apoptosis (programmed cell death) are thought to be intimately linked processes, acting to preserve homeostasis and developmental morphogenesis. Although proteins that regulate apoptosis have been implicated in restraining cell-cycle entry and controlling ploidy (chromosome number), the effector molecules at the interface between cell proliferation and cell survival have remained elusive. Here we show that a new inhibitor of apoptosis (IAP) protein, survivin, is expressed in the G2/M phase of the cell cycle in a cycle-regulated manner. At the beginning of mitosis, survivin associates with microtubules of the mitotic spindle in a specific and saturable reaction that is regulated by microtubule dynamics. Disruption of survivin-microtubule interactions results in loss of survivin’s anti-apoptosis function and increased caspase-3 activity, a mechanism involved in cell death, during mitosis. These results indicate that survivin may counteract a default induction of apoptosis in G2/M phase. The overexpression of survivin in cancer may overcome this apoptotic checkpoint and favour aberrant progression of transformed cells through mitosis.
4- Duffy M. J., O’Donovan N., Brennan D. J., Gallagher W. M. and Ryan B. M. Cancer Lett. 249(1):49-60 (2007)
Survivin is a 16.5 kDa protein overexpressed in almost all malignancies but rarely detected in normal differentiated adult tissues. Functionally, survivin has been shown to inhibit apoptosis, promote cell proliferation and enhance angiogenesis. Consistent with its role in these processes, survivin has been shown to play a key role in cancer progression. Because of the large difference in expression between normal and malignant tissue and its causal role in cancer progression, survivin is currently undergoing intensive investigation as a potential tumor marker. Emerging data suggests that measurement of survivin can aid the early diagnosis of bladder cancer, determine prognosis in multiple cancer types and predict response to diverse anti-cancer therapies. These preliminary findings on the diagnostic, prognostic and predictive potential of survivin should now be confirmed in large prospective trials. Furthermore, assays for the measurement of survivin should be simplified, standardized and evaluated in external quality assurance schemes.
5- Andersen M. H., Pederson L. O., Becker J. C. and thor Straten P. American Association for Cancer Research; 61(3):869-872 (2001)
Identification of a Cytotoxic T Lymphocyte Response to the Apoptosis Inhibitor Protein Survivin in Cancer Patients
During the last decade, a large number of human tumor-associated antigens have been identified that are recognized by CTLs in a MHC-restricted fashion. The apoptosis inhibitor protein survivin is overexpressed in most human cancers, and inhibition of its function results in increased apoptosis. Therefore, this protein may serve as a target for therapeutic CTL responses. Here, using CTL epitopes deduced from survivin, we describe specific T-cell reactivity against this antigen in peripheral blood from chronic lymphatic leukemia patients and in tumor-infiltrated lymph nodes from melanoma patients by ELISPOT analysis. CTL responses against two survivin-deduced peptide epitopes were detected in three of six melanoma patients and three of four chronic lymphatic leukemia patients. No T-cell reactivity was detected in peripheral blood lymphocytes from six healthy controls. Thus, survivin may serve as an important and widely applicable target for anticancer immunotherapeutic strategies.
6- Becker J. C. et al. Cancer Immunol. Immunoother. 61(11):2091-2103 (2012)
Survivin-specific T-cell reactivity correlates with tumor response and patient survival: a phase-II peptide vaccination trial in metastatic melanoma
BACKGROUND: Therapeutic vaccination directed to induce an anti-tumoral T-cell response is a field of extensive investigation in the treatment of melanoma. However, many vaccination trials in melanoma failed to demonstrate a correlation between the vaccine-specific immune response and therapy outcome. This has been mainly attributed to immune escape by antigen loss, rendering us in the need of new vaccination targets.
METHODS: This phase-II trial investigated a peptide vaccination against survivin, an oncogenic inhibitor-of-apoptosis protein crucial for the survival of tumor cells, in HLA-A1/-A2/-B35-positive patients with treatment-refractory stage-IV metastatic melanoma. The study endpoints were survivin-specific T-cell reactivity (SSTR), safety, response, and survival (OS).
RESULTS: Sixty-one patients (ITT) received vaccination therapy using three different regimens. 55 patients (PP) were evaluable for response and survival, and 41/55 for SSTR. Patients achieving progression arrest (CR + PR + SD) more often showed SSTRs than patients with disease progression (p = 0.0008). Patients presenting SSTRs revealed a prolonged OS (median 19.6 vs. 8.6 months; p = 0.0077); multivariate analysis demonstrated SSTR as an independent predictor of survival (p = 0.013). The induction of SSTRs was associated with gender (female vs. male; p = 0.014) and disease stage (M1a/b vs. M1c; p = 0.010), but not with patient age, HLA type, performance status, or vaccination regimen.
CONCLUSION: Survivin-specific T-cell reactivities strongly correlate with tumor response and patient survival, indicating that vaccination with survivin-derived peptides is a promising treatment strategy in melanoma.