Identification and characterization of survivin‐derived H‐2K^b‐restricted CTL epitopes

Abstract

Survivin is overexpressed in several malignancies and in tumor-associated endothelium making it an attractive target for therapeutic cytotoxic T-cell responses. Thus, it would be important to test this notion in preclinical models. Consequently, we screened the murine survivin sequence for potential binding K b -restricted octamer peptide epitopes. Two epitopes, which bind strongly to K b , were selected to test their immunogenicity in vivo.Spleen cells from mice vaccinated by intradermal injection of mature DC pulsed with these peptides displayed reactivity to the respective epitopes. The natural processing and presentation of these epitopes by tumor cells was evident by the killing of murine melanoma cells by vaccination-induced T cells. Subcutaneous challenge with syngeneic melanoma demonstrated the protective immunity of this vaccination. Notably, analysis of the vessel density in subcutaneous tumors revealed that survivin-specific vaccination significantly reduced the number of intratumoral vessels. In summary, we demonstrated the immunogenicity of two K b -restricted peptide epitopes derived from the murine survivin protein; moreover, survivin-specific vaccination not only resulted in a reduction of tumor cells but also the tumor supplying blood vessels. The presented preclinical model for survivin-directed vaccination may serve as a valuable tool to improve already running clinical trials in a syngeneic tumor model. IntroductionIt is well established that peptide epitopes derived from tumorassociated antigens (TAA) can be recognized by CTL in the context of MHC molecules [1]. Consequently, the use of antigenspecific immunotherapy has been explored over the past several years and has revealed that the success of cancer immunotherapy is dependent on using suitable TAA. An ideal TAA should have several important features, i.e. (i) induction of T cells that recognize tumors but not normal cells, (ii) high expression in tumors and tumor patients, and (iii) that the molecule is obligatory for the survival of tumor cells. Recently, survivin has been suggested as a new target for immunotherapy that fits these criteria. Survivin is a member of the inhibitor of apoptosis protein family, which inhibits apoptosis by mitochondrial-dependent caspases [2]. Survivin is overexpressed in numerous solid tumors, including lung, colon, breast, pancreatic, prostate cancer as well as melanoma and hematopoietic malignancies, but is absent in normal, differentiated tissues [3][4][5][6][7]. Thus, overexpression of survivin in cancer cells is associated with decreased overall survival [8][9][10], an increased rate of recurrences, and a reduced apoptotic index of neoplastic cells in vivo [11]. Recently, it has been reported that expression of survivin and the inhibitory T-cell ligand B7-H1 could be used to predict clear cell renal cell carcinoma tumor aggressiveness [12].In addition to its direct role in carcinogenesis, survivin may also play a key role in tumor angiogenesis because it is strongly expressed in endothelial cells duri...

HSP DNAJB8 Controls Tumor-Initiating Ability in Renal Cancer Stem–like Cells

“…However, it is not clear which will bring about a better antitumor effect: targeting CSC antigens or targeting shared antigens. On the basis of this point of view, we compared the immunogenicity of DNAJB8 with that of the well-characterized TAA Survivin (26)(27)(28)(29), as Survivin is expressed in both CSCs/ CICs and non-CSCs/CICs at the same levels (Fig. 5A) and it is a shared antigen.…”

Survivin in skin pathologies

“…As outlined in this review, (i) the involvement of survivin in multiple cellular networks, (ii) its over‐expression which is almost completely restricted to malignant tissues, (iii) the observations that survivin may confer resistance to anti‐cancer therapy and (iv) the role that survivin might play in tumour initiation and/or progression in angiogenesis, make this protein an attractive target for cancer therapy. In skin, most of the anti‐survivin therapeutic strategies have been applied so far for cutaneous melanoma in preclinical animal models (136) as well as clinical trials (3,126,127,137).…”

Cancer-Targeted BikDD Gene Therapy Elicits Protective Antitumor Immunity against Lung Cancer

“…4D, Western blot). A study recently identified a survivin-derived H-2K b -restricted CTL epitopes that could inhibit tumor growth in mouse model (17). We used the survivin-derived peptides as stimulator to activate survivin-specific T-cell population in the splenocytes in ELISpot assay.…”