Immunoglobulin kappa gene repertoire and somatic hypermutation patterns in follicular lymphoma

Smilevska, Tatjana; Tsakou, Eugenia; Hadzidimitriou, Anastasia; Bikos, Vasilis; Stavroyianni, Niki; Laoutaris, Nikolaos; Fassas, Αthanasios; Anagnostopoulos, Αchilles; Papadaki, Theodora; Belessi, Chrysoula; Stamatopoulos, Kostas

doi:10.1016/j.bcmd.2008.06.002

Cited by 13 publications

(14 citation statements)

References 30 publications

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“…In particular, the molecular characterization of Hepatitis C Virus (HCV)-related lymphomas showed that >70% of these cases preferentially use either IGKV3-20 or IGKV3-15 light chains, with a high degree of homology across different lymphomas (11)(12)(13)(14). Similar molecular features have been also found in a proportion of non-HCV-related B-NHLs, including autoimmunity-associated lymphoproliferations (13), diffuse large B-cell lymphomas (15), marginal zone B-cell lymphomas (16,17), follicular lymphomas (18), multiple myeloma (18), and chronic lymphocytic leukemias (18)(19)(20). On these grounds, IGKV3-based vaccines could be used in a considerable fraction of patients with different B-cell lymphoproliferations.…”

Section: Introductionsupporting

confidence: 57%

IGKV3 Proteins as Candidate “Off-the-Shelf” Vaccines for Kappa-Light Chain–Restricted B-Cell Non-Hodgkin Lymphomas

Martorelli¹,

Giusti²,

Re³

et al. 2012

Clinical Cancer Research

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Purpose: An increasing set of B-cell non-Hodgkin lymphomas (B-NHL) show a biased usage of IGKV3-20 and IGKV3-15 immunoglobulin genes, a feature that could be exploited for the development of ready-touse, broadly applicable cancer vaccines.Experimental Design: The immunogenic properties of clonal IGKV3-20 and IGKV3-15 proteins were analyzed with particular focus on their ability to elicit cross-reactive responses against molecularly related IGKV proteins expressed by different B-cell lymphoproliferative disorders.Results: IGKþ lymphoma patients show humoral and T-cell responses to IGKV3-20 and IGKV3-15 proteins and IGKV3-specific cytotoxic T lymphocytes (CTL) can be easily induced ex vivo. IGKV3-20-specific CTLs cross-react against different IGKV3 proteins, an effect mediated by the presence of 21 shared, sometimes promiscuous, T-cell epitopes, presented by common HLA class I allele products, thus assuring a broad HLA coverage of IGKV3-based vaccines. Many natural epitope variants are carried by IGK light chains expressed by a broad spectrum of B-NHLs and we show that IGKV3-20-specific CTLs cross-react also against several of these variant epitopes. Both humoral and CTL-specific responses were induced by KLH-conjugated IGKV3-20 protein in HLA-A2-transgenic mice and coinjection of IGKV3-20-specific CTLs with IGKV3-20þ or IGKV3-15þ lymphoma cells into SCID mice totally prevented tumor growth, thus confirming the ability of these effectors to mediate efficient and cross-reactive cytotoxic responses also in vivo.Conclusions: These results provide the rationale to exploit IGKV3 proteins as "off-the-shelf" vaccines for a large fraction of lymphoma patients. Clin Cancer Res; 18(15); 4080-91. Ó2012 AACR.

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Section: Introductionsupporting

confidence: 57%

IGKV3 Proteins as Candidate “Off-the-Shelf” Vaccines for Kappa-Light Chain–Restricted B-Cell Non-Hodgkin Lymphomas

Martorelli¹,

Giusti²,

Re³

et al. 2012

Clinical Cancer Research

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“…In particular, more than 70% of hepatitis C virus (HCV)-related lymphomas expresses either the IGKV3-20 or the IGKV3-15 light chains, with a high degree of homology across different lymphomas [18][19][20][21]. Similar features have been reported in non-HCV-related lymphoid malignancies, including autoimmunity-associated lymphoproliferations, such as Sjögren's syndrome [22], marginal zone B-cell lymphomas [23,24], follicular lymphomas [25], multiple myeloma [25], and chronic lymphocytic leukemias [25][26][27]. IGKV3-20 and IGKV3-15 are immunogenic ex vivo and capable of eliciting memory T-cell responses in NHL patients [28].…”

Section: Introductionmentioning

confidence: 80%

“…The adapter was cloned in pBK-CMV-VK 3-20 using SalI/NotI restriction sites. A synthetic GA 25 sequence was excised from the UB-R-GFPGA25 plasmid [32] using the BglII/BamHI restriction enzymes and then cloned in the BamHI site of pBK-CMV-VK 3-20 /ADAPTER generating pBK-CMV-VKGA 25 . The VKGA 25 coding sequence was then excised using the HindIII/NotI restriction sites and cloned in the eukaryotic expression vector 3XFLAG-CMV-10 (SigmaAldrich, St. Louis, MO).…”

Section: Plasmidsmentioning

confidence: 99%

Remodeling of the epitope repertoire of a candidate idiotype vaccine by targeting to lysosomal degradation in dendritic cells

Martorelli

Coppotelli

Muraro

et al. 2011

Cancer Immunol Immunother

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The generation of efficacious vaccines against self-antigens expressed in tumor cells requires breakage of tolerance, and the refocusing of immune responses toward epitopes for which tolerance may not be established. While the presentation of tumor antigens by mature dendritic cells (mDC) may surpass tolerance, broadening of the antigenic repertoire remains an issue. We report that fusion of the candidate idiotype vaccine IGKV3-20 to the Gly-Ala repeat (GAr) of the Epstein-Barr virus nuclear antigen (EBNA)-1 inhibits degradation by the proteasome and redirects processing to the lysosome. mDCs transduced with a recombinant lentivirus encoding the chimeric idiotype efficiently primed CD4+ and CD8+ cytotoxic T-cell (CTL) responses that lysed autologous blasts expressing IGKV3-20 or pulsed with IGKV3-20 synthetic peptides, and HLA-matched IGKV3-20-positive tumor cell lines. Comparison of the cytotoxic response of CD4+ and CD8+ T lymphocytes activated by mDCs expressing the wild-type or chimeric IGKV3-20 reveled largely non-overlapping epitope repertoires in both CD4+ and CD8+ effectors. Thus, fusion to the GAr may provide an effective means to broaden the immune response to an endogenous protein by promoting the presentation of antigenic epitopes that require a lysosome-dependent processing step.

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“…In this respect, we recently characterized the immunogenic properties of IGKV3-20 and IGKV3-15 proteins [56], highly expressed, as mentioned above, in HCV-associated lymphomas autoimmunity-associated lymphoproliferations, DLBCL, MZL, FL, and CLL ( Figure 7) [30,58,[68][69][70][71][72][73]. We found IGKV3-20 and IGKV3-15-specific T-cell and humoral responses in NHL patients, and proved that these 2 proteins are immunogenic ex vivo.…”

Section: Lessons From Igkv3-20mentioning

confidence: 99%

“…In this respect, a recent paper from Weng et al, selected the T-cell leukemia/lymphoma 1 (TCL1) oncoprotein as an aberrantly expressed antigen in many B-cell malignancies, including FL, CLL, MCL, DLBCL, and SMZL, and identified TCL1 [71][72][73][74][75][76][77][78] as the minimal epitope that binds to HLA-A*0201. They were able to generate peptide-specific CTLs lines from HLA-A*0201 healthy donors and patients, and these CTLs can efficiently kill lymphoma cell lines and primary human lymphoma cells [63].…”

Section: Ighv1-69 As a Promising Candidate For A Shared Immunotherapymentioning

confidence: 99%

1086 IGHV1-69 as a Promising Candidate for the Development of a Shared Immunotherapy to B-cell Lymphomas

Muraro¹,

Martorelli²,

Bomben³

et al. 2012

European Journal of Cancer

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B-cell Non-Hodgkin Lymphomas (B-NHL) are a heterogeneous group of cancers, broadly diffused worldwide and often relapsing after standard treatment and rituximab. Therapeutic vaccines targeting B-NHL idiotype (Id) represent a promising approach to maintain the complete response induced by standard treatments. However, customized idiotypic vaccination still remains a non-approved, experimental therapeutic option, mostly due to the personalized use and penalized by the lack of reliable clinical or biological markers of patient eligibility and responsiveness. Nevertheless, the molecular characterization of different lymphoid tumor histotypes revealed a set of stereotyped immunoglobulins among distinct B-cell lymphoma types. On this ground, we focused our attention on the IGHV1-69 protein, frequently expressed in HCV-associated lymphomas, chronic lymphocytic leukaemia, and auto-immunity related lymphoproliferations, and we characterized the ex vivo immunogenicity of this protein.Seventy IGHV1-69 sequences obtained from patients affected by different B-NHLs or pre-malignant lymphoproliferations were compared to design an optimized sequence characterized by the highest degree of similarity among studied cancers, and thus CDR3 hypervariable region free. Within this "immunogenically" optimized sequence, we identified 13 potential HLA class-I cytotoxic T lymphocyte (CTL) epitopes and synthesized the corresponding pentamers (Pent). We assessed by flow cytometry the presence and extent of epitope-specific T-cell responses in peripheral blood of patients with IGHV1-69 + B-cell lymphoproliferative disorders and healthy donors, and validated these data in IFN-γ ELISPOT (Enzyme-linked immunosorbent spot) assays. Finally, we boosted in vitro IGHV1-69-specific responses by stimulating peripheral blood lymphocytes (PBL) from donors and patients with different protocols for the generation of epitope-specific CTL cultures.Interestingly, the IGHV1-69 Pent + population observed in patients' samples was generally larger than in donors, supporting the existence of spontaneous memory T-cell responses against IGHV1-69, at least for some HLA-restrictions. Surprisingly, in patients' samples, IGHV1-69-recognizing T cells displayed higher IFN-γ release in ELISPOT assays compared to viral-specific T cells. Moreover, we obtained peptide-specific CTL lines, which showed a weak but specific lysis against peptide-pulsed targets, especially when derived from patients' PBLs. In addition, we were able to generate IGHV1-69-epitope specific CTL clones from healthy donors CD8 + T cells, employing synthetic artificial APC, developed to elicit and expand low-avidity tumor-directed human CTL lines. Finally, IGHV1-69-induced CTL lines showed specific lysis also towards an IGHV1-69 naturally expressing cell line, suggesting that IGHV1-69 memory T-cell responses could be boosted for therapeutic purposes.These results show that IGHV1-69 constitutes a potential target for the development of a subset-specific Id vaccine. Furthermore, multimer (tetramers...

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Immunoglobulin kappa gene repertoire and somatic hypermutation patterns in follicular lymphoma

Cited by 13 publications

References 30 publications

IGKV3 Proteins as Candidate “Off-the-Shelf” Vaccines for Kappa-Light Chain–Restricted B-Cell Non-Hodgkin Lymphomas

IGKV3 Proteins as Candidate “Off-the-Shelf” Vaccines for Kappa-Light Chain–Restricted B-Cell Non-Hodgkin Lymphomas

Remodeling of the epitope repertoire of a candidate idiotype vaccine by targeting to lysosomal degradation in dendritic cells

1086 IGHV1-69 as a Promising Candidate for the Development of a Shared Immunotherapy to B-cell Lymphomas

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