Human TH17 Immune Cells Specific for the Tumor Antigen MAGE-A3 Convert to IFN-γ–Secreting Cells as They Differentiate into Effector T Cells <i>In Vivo</i>

Hamaï, Ahmed; Pignon, Pascale; Raimbaud, Isabelle; Duperrier-Amouriaux, Karine; Senellart, Hélène; Hiret, Sandrine; Douillard, Jean-Yves; Bennouna, Jaafar; Ayyoub, Maha; Valmori, Danila

doi:10.1158/0008-5472.can-11-3432

Cited by 31 publications

(35 citation statements)

References 21 publications

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“…Briefly, these mice are H-2 Class I and IA Class II knockout, and their CD8 T and CD4 T cells are restricted by the sole HLA-A*0201 and HLA-DR1*0101 molecules, respectively. 11,15 For D393-CD20 [28][29][30][31][32][33][34][35][36][37][38][39][40][41][42][43][44][45][46][47] (20mer) and D393-CD20 33-41 (9mer) immunization, mice were injected twice with 100 lg of D393-CD20 20mer or 50 mg of D393-CD20 9mer were emulsified in incomplete Freund adjuvant (IFA, Sigma-Aldrich). All peptide vaccinations were done subcutaneously at the base of the tail at Days 1 and 14.…”

Section: Mouse and Vaccinationsmentioning

confidence: 99%

“…To evaluate the presence of D393-CD20 specific T cell in the human repertoire, the D393-CD20 [28][29][30][31][32][33][34][35][36][37][38][39][40][41][42][43][44][45][46][47] 20mer-peptide overlapping the splicing site was used to stimulate T cells. For this purpose, peripheral blood lymphocytes of healthy volunteers were in vitro stimulated twice using 10 mmol/L of D393-CD20 [28][29][30][31][32][33][34][35][36][37][38][39][40][41][42][43][44][45][46][47] in 96 well microplates during 14 days as described in the material and method section.…”

Section: D393-cd20 Isoform Protein Expression and Immunogenicitymentioning

confidence: 99%

“…The three first amino-acids used to name these peptides are indicated in boldface. T cell lines were obtained from healthy donors' PBMCs after two rounds of in vitro stimulation in microplates with 10 lg/mL of D393-CD20 [28][29][30][31][32][33][34][35][36][37][38][39][40][41][42][43][44][45][46][47] peptide. Specific responses were assessed by CD4 and IFN-g staining.…”

Section: Tumor Immunologymentioning

confidence: 99%

“…To assess the capacity of the 20mer long peptide D393-CD20 [28][29][30][31][32][33][34][35][36][37][38][39][40][41][42][43][44][45][46][47] (LP) to prime a specific T cell response in vivo, we performed a peptide immunization in HLA-A2/HLA-DR1 transgenic mice and specific T cell responses were measured by ex vivo IFN-g ELISPOT assay. As shown in Figure 5a, specific CD4 T cell responses were induced in vivo against the D393-CD20 28-47 LP and against four of the six D393-CD20 derived 15mer peptides supporting that these peptides effectively binds to HLA-DR1 molecules.…”

Section: Tumor Immunologymentioning

confidence: 99%

“…24 We then evaluated the capacity of the D393-CD20 28-47 long peptide (LP) to prime HLA-A2-restricetd CTL response. To this end, mice were immunized either with the D393-CD20 [28][29][30][31][32][33][34][35][36][37][38][39][40][41][42][43][44][45][46][47] LP or with the HLA-A2-restricted D393-CD20 derived short peptide D393-CD20 [33][34][35][36][37][38][39][40][41] (SP). As shown in Figure 5b, higher IFN-g producing specific-CTL were detected ex vivo after immunization with the D393-CD20 28-47 LP than with the SP.…”

Section: Tumor Immunologymentioning

confidence: 99%

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CD20 alternative splicing isoform generates immunogenic CD4 helper T epitopes

Vauchy

Gamonet

Ferrand

et al. 2014

Intl Journal of Cancer

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Cancer-specific splice variants gain significant interest as they generate neo-antigens that could be targeted by immune cells. CD20, a membrane antigen broadly expressed in mature B cells and in B cell lymphomas, is subject to an alternative splicing named D393-CD20 leading to loss of membrane expression of the spliced isoform. D393-CD20 expression is detectable in transformed B cells and upregulated in various lymphoma B cells. In this study, we show that D393-CD20 is translated in malignant B cells and that D393-CD20 specific CD4 T cells producing IFN-c are present in B-cell lymphoma patients. Then, we have investigated whether the 20mer D393-CD20 peptide spanning the splicing site might be targeted by the immune system and we have shown that D393-CD20-specific CD4 Th1 clones could directly recognize malignant B cell lines and kill autologous lymphoma B cells indicating that D393-CD20-derived epitopes are naturally processed and presented on tumor cells. Finally, D393-CD20 peptide-based vaccination induced specific CD8 and CD4 T cell responses in HLA-humanized transgenic mice suggesting the presentation of D393-CD20 derived peptides on both HLA Class-I and -II. These findings support further investigations on the potential use of D393-CD20 directed specific immunotherapy in B cell malignancies.The effective discovery of clinically relevant tumor antigens holds a fundamental role for the development of new diagnostic tools and anticancer immunotherapies. Generally, tumor antigens are classified as unique antigens derived from point mutations or as shared antigens. The shared antigens are further divided into tumor-specific antigens, differentiation antigens and overexpressed antigens. The prioritization of cancer antigens is based on criteria such as immunogenicity, specificity, oncogenicity. 1 One mechanism that would lead to such priority targets could be alternative splicing. Alternative splicing can change the structure of mRNA by inclusion or skipping of exons, and this may alter the function, stability or binding properties of the encoded protein. 2 Aside from its role in physiological cell adaptation, alternative splicing has been shown to occur in human diseases, including cancer. 3 Particularly, the splice variants differ between cancer and normal corresponding tissues. 4,5 Cancerspecific splice variants are thus of significant interest as they may be involved in pathogenesis and may further potentially be used as biomarkers and generate novel targets for therapy. Because immune recognition of antigenic epitopes is highly specific, alternative exon splicing could provide the structural basis for expression of novel amino-acid sequences not subject to self repertoire tolerance.We previously identified an alternative transcript of the B cell lineage membrane receptor CD20. This alternative transcript lacks 168 nucleotides within Exon 3 to 7 compared to the wild-type CD20 transcript and referred thereafter as D393-CD20. 6 D393-CD20 translation gives rise to a protein lacking the extracellular domain and ...

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Section: Mouse and Vaccinationsmentioning

confidence: 99%

Section: D393-cd20 Isoform Protein Expression and Immunogenicitymentioning

confidence: 99%

Section: Tumor Immunologymentioning

confidence: 99%

Section: Tumor Immunologymentioning

confidence: 99%

Section: Tumor Immunologymentioning

confidence: 99%

See 3 more Smart Citations

CD20 alternative splicing isoform generates immunogenic CD4 helper T epitopes

Vauchy

Gamonet

Ferrand

et al. 2014

Intl Journal of Cancer

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Functional human Th17 clones with WT1-specific helper activity

Tachino

Fujiki

Oka

et al. 2012

Cancer Immunol Immunother

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Th17 plays important roles in the pathogenesis of various inflammatory and autoimmune diseases. Although the importance of Th17 in tumor immunity has also been suggested, precise roles of tumor-associated antigen-specific Th17 still remain poorly understood, especially in humans. We previously identified WT1332, a 16-mer helper epitope derived from tumor-associated antigen Wilms' tumor gene 1 (WT1) product, and WT1332-specific Th1 clones were established. In the present study, WT1-specific Th17 clones were established by the stimulation of peripheral blood mononuclear cells with the WT1332 helper peptide under human Th17-polarizing conditions. The WT1-specific Th17 clone exhibited the helper function for proliferation of conventional CD4(+) T cells in the antigenic stimulation-specific manner. This is the first report of establishment of functional Th17 clones with both antigen (WT1332) specificity and antigen-specific helper activity. Th17 clones established here and the method to establish antigen-specific Th17 clones should be a useful tool to further analyze the roles of human Th17 in tumor immunity.

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Activation of CD1d-restricted natural killer T cells can inhibit cancer cell proliferation during chemotherapy by promoting the immune responses in murine mesothelioma

Yun

Tagawa

et al. 2014

Cancer Immunol Immunother

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We studied the impact of natural killer T (NKT) cell activation by alpha-galactocysylceramide (α-GalCer, α-GC) on cancer cell repopulation during chemotherapy in murine mesothelioma. The number of NKT cells was found to be increased during the development of murine mesothelioma. NKT cells specifically recognize α-GC through CD1d resulting in their activation and expansion. Tumor-bearing mice were treated with chemotherapy once weekly, and α-GC was followed after each cycle of chemotherapy. Anti-tumor effect was evaluated on wild-type (WT) and CD1d knockout (CD1dKO) mice. Cancer cell proliferation and apoptosis were evaluated by Ki67 and TUNEL immunohistochemistry. CD4(+) and CD8(+) T cell proportion and activation in tumor, spleen, draining lymph node and peripheral blood were determined by flow cytometry, and gene expression of activated T cell-related cytokines was quantified by reverse transcription PCR. NKT cells were identified by CD1d-α-GC-tetramer staining. In WT mice, tumor growth delay was achieved by cisplatin (Cis), and this effect was improved in combination with α-GC, but α-GC alone had little effect. Cancer cell proliferation during chemotherapy was significantly inhibited by α-GC, while cancer cell death was significantly upregulated. α-GC following chemotherapy resulted in NKT cell expansion and an increase of interferon-γ production in the draining lymph node, blood and spleen. Gene expression of immune-associated cytokines was upregulated. Strikingly, the percentage of inducible T cell co-stimulator(+)CD4 T cells, Th17/Tc17 cells increased in splenocytes. In CD1d KO mice, however, Cis alone was less effective and Cis + α-GC provided no additional benefit over Cis alone. α-GC alone had minimal effect in both mice. NKT activation between cycles of chemotherapy could improve the outcome of mesothelioma treatment.

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Human TH17 Immune Cells Specific for the Tumor Antigen MAGE-A3 Convert to IFN-γ–Secreting Cells as They Differentiate into Effector T Cells In Vivo

Abstract: The role of T H 17 cells in cancer is being investigated, but the existence of tumor antigen-specific T H 17 cells has yet to be ascertained. Here, we report the first description of a spontaneous

Cited by 31 publications

References 21 publications

CD20 alternative splicing isoform generates immunogenic CD4 helper T epitopes

CD20 alternative splicing isoform generates immunogenic CD4 helper T epitopes

Functional human Th17 clones with WT1-specific helper activity

Activation of CD1d-restricted natural killer T cells can inhibit cancer cell proliferation during chemotherapy by promoting the immune responses in murine mesothelioma

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