IGKV3 proteins as candidate "off-the-shelf" vaccines for kappa-light chain-restricted B-cell non-Hodgkin lymphomas.
OBJECTIVE
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-to-use, broadly applicable cancer vaccines.


METHODS
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
IGK+ 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 IGKV3-20+ or IGKV3-15+ 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.
Cancer Bio-Immunotherapy Unit, IRCCS-National Cancer Institute, Aviano, Italy.
Debora
D
Martorelli
Massimo
M
Guidoboni
Valli
V
De Re
Elena
E
Muraro
Riccardo
R
Turrini
Anna
A
Merlo
Elisa
E
Pasini
Laura
L
Caggiari
Luca
L
Romagnoli
Michele
M
Spina
Roberta
R
Mortarini
Daniela
D
Gasparotto
Mario
M
Mazzucato
Antonino
A
Carbone
Antonio
A
Rosato
Andrea
A
Anichini
Riccardo
R
Dolcetti
D000328:Adult; D000368:Aged; D000595:Amino Acid Sequence; D000818:Animals; D019496:Cancer Vaccines / Q000008:administration & dosage / Q000276:immunology*; D045744:Cell Line, Tumor; D003429:Cross Reactions / Q000276:immunology; D004797:Enzyme-Linked Immunosorbent Assay; D018984:Epitopes, T-Lymphocyte / Q000276:immunology; D005260:Female; D005434:Flow Cytometry; D006680:HLA Antigens / Q000235:genetics / Q000276:immunology; D015789:HLA-A2 Antigen / Q000235:genetics / Q000276:immunology; D006801:Humans; D056724:Immunity, Humoral / Q000276:immunology*; D007145:Immunoglobulin kappa-Chains / Q000276:immunology*; D016393:Lymphoma, B-Cell / Q000276:immunology* / Q000473:pathology / Q000628:therapy; D008297:Male; D051379:Mice; D016513:Mice, SCID; D008822:Mice, Transgenic; D008875:Middle Aged; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology / Q000378:metabolism / Q000637:transplantation; D023041:Xenograft Model Antitumor Assays
D019496:Cancer Vaccines; D018984:Epitopes, T-Lymphocyte; D006680:HLA Antigens; D015789:HLA-A2 Antigen; D007145:Immunoglobulin kappa-Chains