Molecular modification of idiotypes from B-cell lymphomas for expression in mature dendritic cells as a strategy to induce tumor-reactive CD4+ and CD8+ T-cell responses.
Most non-Hodgkin B-cell lymphomas (NHLs) are characterized by the clonal expansion of a single cell expressing a unique rearranged immunoglobulin gene. This idiotype (Id) is a tumor-specific antigen that can be immunologically targeted. The therapeutic efficacy of Id-based vaccines correlates best with detection of cellular immune responses, although these have not been as well characterized as the humoral responses. This study exploited a molecular approach to modify the Id of 38C13 lymphoma for processing via class I and II antigen-processing pathways and evaluated protein expression in dendritic cells (DCs) to simultaneously stimulate tumor reactive CD8(+) and CD4(+) lymphocytes. Recombinant vaccinia viruses (rVVs) were constructed, coding for Id fused with the targeting signal of the lysosomal-associated membrane protein1 (Id-LAMP1) to promote antigen presentation in the context of major histocompatibility complex (MHC) class II. Mature DCs infected with rVV/Id-LAMP1 elicited both CD4(+) and CD8(+) Id-specific T cells and protected animals from tumor challenge. Id-specific CD8(+) cells were required to mediate the effector phase of a therapeutic response, and CD4(+) cells were beneficial in the induction phase of the response. These results demonstrate that fusing Id to LAMP1 enhances CD8(+) and CD4(+) Id-specific responses for NHLs and may be useful therapeutically.
Muraro
Sara
S
Cancer Immunotherapy and Gene Therapy Program, Istituto Scientifico H. S. Raffaele, Via Olgettina 58, 20132-Milano, Italy.
Bondanza
Attilio
A
Bellone
Matteo
M
Greenberg
Philip D
PD
Bonini
Chiara
C
D000818:Animals; D015703:Antigens, CD / Q000235:genetics / Q000276:immunology; D000951:Antigens, Neoplasm / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D045744:Cell Line, Tumor; D002999:Clone Cells / Q000276:immunology; D003713:Dendritic Cells / Q000276:immunology* / Q000378:metabolism; D005260:Female; D000949:Histocompatibility Antigens Class II; D007130:Immunoglobulin Idiotypes / Q000276:immunology*; D016393:Lymphoma, B-Cell / Q000276:immunology* / Q000473:pathology / Q000628:therapy; D052118:Lysosomal-Associated Membrane Protein 1; D051907:Lysosomal Membrane Proteins; D051379:Mice; D008809:Mice, Inbred C3H; D011993:Recombinant Fusion Proteins / Q000276:immunology; D014616:Vaccinia virus / Q000235:genetics
D015703:Antigens, CD; D000951:Antigens, Neoplasm; D000949:Histocompatibility Antigens Class II; D007130:Immunoglobulin Idiotypes; D052118:Lysosomal-Associated Membrane Protein 1; D051907:Lysosomal Membrane Proteins; D011993:Recombinant Fusion Proteins