Identification of immunogenic LY6K long peptide encompassing both CD4+ and CD8+ T-cell epitopes and eliciting CD4+ T-cell immunity in patients with malignant disease

Yusuke Tomita, Akira Yuno, Hirotake Tsukamoto, Satoru Senju, Yasuhiro Kuroda, Masatoshi Hirayama, Yuya Imamura, Junji Yatsuda, Mohammad Abu Sayem, Atsushi Irie, Akinobu Hamada, Hirofumi Jono, Koji Yoshida, Takuya Tsunoda, Yataro Daigo, Hirotsugu Kohrogi, Yoshihiro Yoshitake, Yusuke Nakamura, Masanori Shinohara, Yasuharu Nishimura, Yusuke Tomita, Akira Yuno, Hirotake Tsukamoto, Satoru Senju, Yasuhiro Kuroda, Masatoshi Hirayama, Yuya Imamura, Junji Yatsuda, Mohammad Abu Sayem, Atsushi Irie, Akinobu Hamada, Hirofumi Jono, Koji Yoshida, Takuya Tsunoda, Yataro Daigo, Hirotsugu Kohrogi, Yoshihiro Yoshitake, Yusuke Nakamura, Masanori Shinohara, Yasuharu Nishimura

Abstract

Identification of peptides that activate both tumor-specific helper T (Th) cells and cytotoxic T lymphocytes (CTLs) are important for the induction of effective antitumor immune responses. We focused on a long peptide (LP) derived from lymphocyte antigen 6 complex locus K (LY6K) encompassing both candidate Th epitopes and a known CTL epitope. Using IFNγ ELISPOT assays as a marker of activated T cells, we studied the immunogenicity and cross-priming potential of LY6K-LP, assaying human immune cell responses in vitro and immunologic activities in HLA-A24 transgenic mice in vivo. We identified LY6K172-191-LP as an effective immunogen spanning naturally processed epitopes recognized by T helper type 1 (Th1) cells and CTLs. LY6K-specific CTLs were induced through cross-presentation of LY6K172-191-LP in vitro and in vivo. In addition, LY6K172-191-LP enhanced induction of LY6K-specific CTLs among the peripheral blood mononuclear cells (PBMCs) of head-and-neck malignant tumor (HNMT) patients. LY6K172-191-LP-specific Th1 immunologic response following 1 week in vitro stimulation of PBMCs with LY6K172-191-LP were detected in 16 of 21 HNMT patients (76%) vaccinated with CTL-epitope peptides and 1 of 11 HNMT patients (9%) prior to vaccination, but not in 9 healthy donors. Our results are the first to demonstrate the presence of LY6K-specific Th1 cell responses in HNMT patients and underscore the possible utility of LY6K172-191-LP for the induction and propagation of both LY6K-specific Th1 cells and CTLs.

Keywords: CTL epitope; Th1 cells; cancer testis antigen; cross-presentation; cross-priming; head and neck cancer; helper T-cell epitope; immunotherapy; lymphocyte antigen 6 complex locus K.

Figures

https://www.ncbi.nlm.nih.gov/pmc/articles/instance/4203508/bin/onci-3-e28100-g1.jpg
Figure 1. Induction of LY6K-specific helper T cells from healthy donors. (A–F) LY6K-specific helper T (Th) cells were generated from healthy donors (HDs) by stimulating purified CD4+ cells with LY6K119–142-LP or LY6K172–191-LP, as indicated. The number of IFNγ-producing Th cells was analyzed by ELISPOT assay. Data are presented as the mean ± SD of triplicate assays. The HLA class-II genotype is indicated above the panels. The underlined HLA-Class II allele encodes the element presenting the peptides to Th cells. (A) Induction of HLA-DP5-restricted LY6K119–142-LP-specific Th cells in donor HD1. Data are from at least 3 independent experiments with representative results shown. The Th cells were restimulated with autologous peripheral blood mononuclear cells (PBMCs; left panel) or L-cells (engineered to express the indicated HLA molecule) pulsed with LY6K119–142-LP antigen presenting cells (APCs; right panel). An Epstein‒Barr virus-derived nuclear antigen (EBNA-DP5 LP) was used as a control LP. B-F. Induction of HLA-restricted LY6K119–142-LP (B and C) or LY6K172–191-LP (D–F) specific Th cells, similar to (A) (above). (B) Induction of HLA-DR8-restricted LY6K119–142-LP-specific Th cells in donor HD2. (C) Induction of HLA-DR15-restricted LY6K119–142-LP-specific Th cells in donor HD3. (D and E) HLA-DR15-restricted LY6K172–191-LP-specific Th cells were generated from HD2 and HD3. (F). HLA-DQ-restricted LY6K172–191-LP-specific Th cells were generated from a DR15-negative HD4. LP, long peptide.
https://www.ncbi.nlm.nih.gov/pmc/articles/instance/4203508/bin/onci-3-e28100-g2.jpg
Figure 2. LY6K-LPs encompass naturally processed Th-cell epitopes. (A and B). The number of IFNγ-producing healthy donor (HD) derived helper T (Th) cells stimulated by antigen-presenting dendritic cells (DCs) loaded with recombinant full-length lymphocyte antigen 6 complex locus K (LY6K) protein was analyzed by ELISPOT assay. (A) HLA-DP5-restricted LY6K119–142-LP-specific bulk helper T (Th) cells established from HD1 specifically recognized autologous DCs loaded with recombinant LY6K protein (left panel). Representative data are shown from 3 independent experiments with similar results achieved. (B) HLA-DR15 (left) or HLA-DQ (right)-restricted LY6K172–191-LP-specific Th-clone (from HD2 and HD4, respectively) recognized autologous DCs loaded with a recombinant LY6K protein. Representative data are shown from 5 independent experiments with similar results achieved. The cognate LY6K-LPs were used as positive controls in the IFNγ ELISPOT assays. APC, antigen-presenting cells; LP, long peptide.
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Figure 3. Presence of LY6K-LPs-specific Th1 cells in the peripheral blood of LY6K177–186-A24 SP vaccinated HNMT patients. (A–D). Fresh peripheral blood mononuclear cells (PBMCs) derived from patients vaccinated with LY6K177–186-A24 SP (refer to Table 1) were stimulated with a mixture of LY6K119–142-LP and LY6K172–191-LP plus IL-2 and IL-7 in vitro. After 1 wk, the frequency of LY6K-LP-specific T cells was detected by IFNγ ELISPOT assay. (B and C) LY6K-LP-specific-Th1 cell responses were assessed in 23 HNMT patients. Samples were tested from 21 HNMT patients vaccinated with LY6K177–186-A24 SP (After Vac.), 11 HNMT patients prior to vaccination (Before Vac.), and 9 healthy donors as controls. (B) Th-cell responses to the indicated LY6K-LP as IFNγ spots per 105 cells detected after background subtraction. Each dot represents an individual donor. Horizontal lines denote median values, and P values represent statistical results from a nonparametric Mann‒Whitney U test. n.s., not significant. (C) Column graph showing proportion of patients and healthy donors responding to LY6K172–191-LP (from B) prior to and after vaccination. P values were calculated using Fisher’s exact probability test. (D) HLA class II-restriction of LY6K-LP-specific Th1 cells. Fresh PBMCs stimulated with LY6K-LPs for 1 wk were re-stimulated with each LY6K-LP (LY6K119–142-LP or LY6K172–191-LP, as indicated) in the presence (or absence, first column) of monoclonal antibodies (mAbs) specific to HLA-DR, -DP, -DQ class II or HLA-Class I. SP, short peptide; LP, long peptide.
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Figure 4. LY6K172–191-LP induces efficient expansion of LY6K177–186-A24 SP-specific CD8+ T-cells in vitro and in vivo. (A and B) Autologous dendritic cells (DCs) uptake and cross-present LY6K172–191-LP to LY6K177–186-A24 SP-specific CD8+ cytotoxic T lymphocytes (CTLs) derived from healthy donor (HD3). (A) Unfixed or fixed DCs were pulsed for 3 h with LY6K172–191-LP or LY6K177–186-A24 SP. Bulk HD3-derived LY6K177–186-A24 SP-specific CTLs were co-cultured with the pulsed DCs for 6 h and responses were measured by intracellular IFNγ staining and flow cytometry. Representative data from 3 independent experiments with similar results are shown. (B) HD3-derived LY6K177–186-A24 SP-specific bulk CTLs were stimulated with LY6K172–191-LP (middle panel) or irrelevant LP (right panel)-pulsed autologous DCs in vitro. The peptide treated cells were stained with a HLA-A24/LY6K177–186-specific tetramer in combination with an anti-CD8 mAb at the indicated time points. A pre-treatment (d0) control is shown in the left panel. Stained cells were analyzed by flow cytometry gating on CD8+ T cells. Representative data are from 3 independent experiments with similar results achieved. (C and D) LY6K172–191-LP expands LY6K177–186-A24 SP-specific CTLs derived from vaccinated HNMT patients. Fresh PBMCs from the HNMT patient (HNMT108) vaccinated with LY6K177–186-A24 SP were cultured with LY6K172–191-LP. On day 0 (ex vivo) and day 7, the PBMCs were stained with a HLA-A24/LY6K177–186-specific tetramer or control tetramer and analyzed by flow cytometry gating on CD8+ T cells. (C) Dot plot (left) of tetramer+ CD8+ T cells . On day 7, the frequency of IFNγ-expressing LY6K177–186-A24 SP-specific CTLs was also detected by ELISPOT assay (bar graph). Representative data from 4 vaccinated HNMT patients (refer to Table 1, HNMT43, 105, 108, and 110) with similar results achieved. (D) The increases (fold increase) in proportion of CD8+ tetramer+ cells (from C) are shown. E. LY6K172–191-LP cross-priming of CTLs in vitro. PBMCs obtained from HD3 were incubated with LY6K172–191-LP for 2 wk and LY6K172–191-LP was added on d0 and d7. Cells were harvested d14 and stained with a HLA-A24/LY6K177–186-specific tetramer. Representative data are from 3 independent experiments (both technical and biological replicates) with similar results achieved. (F) Induction of LY6K177–186-A24 SP-specific CTLs in mice immunized with LY6K172–191-LP. HLA-A24-expressing transgenic mice were immunized with LY6K172–191-LP. After the third vaccination with LY6K172–191-LP, murine CD8+ T-cells in the inguinal lymph nodes were stimulated with bone marrow-derived DCs pulsed with LY6K177–186-A24 SP. The number of IFNγ-producing murine CD8+ T-cells was analyzed by ELISPOT. Representative data are from 8 independent experiments with similar results achieved. HNMT, head and neck malignant tumor; LP, long peptide; SP, short peptide.
https://www.ncbi.nlm.nih.gov/pmc/articles/instance/4203508/bin/onci-3-e28100-g5.jpg
Figure 5. The synergistic effect of LY6K-LPs on induction of LY6K177–186-A24 SP-specific CTLs. (A) LY6K119–142-LP-specific or LY6K172–191-LP-specific bulk CD4+ T cells and LY6K177–186-A24 SP-specific bulk CD8+ T cells derived from HLA-A24+/DR15+ HD3 were cultured with autologous DCs in the presence of LY6K177–186-A24 SP (SP) alone, LY6K177–186-A24 SP + Control LP (Control LP + SP), or LY6K177–186-A24 SP + LY6K-LP (LY6K-LP + SP) without cytokine for 1-wk. The cultured cells were then stained with a PE-labeled HLA-A24/LY6K177–186-specific tetramer and a FITC-labeled anti-CD8 antibody and analyzed by flow cytometry. “Pre-stimulation” indicates the absolute number of tetramer+ CD8+ T cells/well of LY6K177–186-A24 SP-specific bulk CD8+ T cells in the healthy donor line. Data are the mean ± SD of triplicate assays. Representative data shown are from 3 independent experiments with similar results achieved. (B) Fresh PBMCs obtained from HNMT43 vaccinated with LY6K177–186-A24 SP were plated in a 96-well, round-bottomed culture plate (1 × 105 cells/well) in 10 μg/mL LY6K177–186-A24 SP alone, LY6K177–186-A24 SP + control LP, LY6K177–186-A24 SP + LY6K119–142-LP or LY6K177–186-A24 SP + LY6K172–191-LP without addition of cytokines. On day 7, cells were stained with a HLA-A24/LY6K177–186-specific tetramer and anti-CD8 antibody and analyzed by flow cytometry. Representative HLA-A24/LY6K177–186-specific tetramer staining is shown (dot plots). (C) Absolute number of tetramer+ CD8+ cells/well. Data are the mean ± SD of triplicate assays. Representative data are from 3 independent experiments with similar results achieved.

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