Synergistic enhancement of antitumor immunity with adoptively transferred tumor-specific CD4+ and CD8+ T cells and intratumoral lymphotactin transgene expression.
The lack of efficient T-cell infiltration of tumors is a major obstacle to successful adoptive T-cell therapy. We have shown that transplanted SP2/0 myeloma tumors that have been engineered to express lymphotactin (Lptn) invariably regress under the influence of infiltrating XCR1+T cells and neutrophils. Herein, we characterize these T cells and investigate their therapeutic efficacy, either alone or with Lptn gene therapy. After stimulation with SP2/0 cells, these T cells were CD25+FasL+L-selectin-, expressed XCR-1, and were chemoattracted by Lptn in vitro. They comprised 66% CD4+ Th1 and 33% CD8+ Tc1 cells, both of which expressed significant amounts of IFN-gamma, perforin, and tumor necrosis factor-alpha, but not interleukin-4. The CD4+ Th1 and CD8+ Tc1 cells, which were inhibited and stimulated, respectively, for proliferation with Lptn signaling, displayed 38 and 84% specific killing, respectively, for Ia(d)/H-2K(d)-expressing SP2/0 tumor cells (E:T ratio, 100). In vivo, combined intratumoral Lptn gene transfer and adoptive immunotherapy with these CD4+ and CD8+ T cells eradicated well-established SP2/0 tumors in six of eight mice, and dramatically slowed tumor growth in the other two mice. Cell tracking using labeled T cells confirmed that these cells infiltrated better into the Lptn-expressing tumors than non-Lptn-expressing ones. Control or Lptn adenoviral treatments by themselves did not alter the lethal outcome for tumor-bearing mice, nor did T-cell therapy by itself, although the latter two treatments did slow its time frame. Combined Lptn gene transfer and adoptive CD4+ or CD8+ cell transfers were not nearly as efficacious as the combined Lptn gene and unfractionated T-cell transfers. Taken together, our data provide solid evidence of a potent synergy between adoptive CD4+ and CD8+ T-cell therapy and Lptn gene transfer into tumor tissues, which culminated in the eradication of well-established tumor masses.
Huang
Hui
H
Research Unit, Saskatchewan Cancer Agency, Departments of Oncology, University of Saskatchewan, Saskatoon, Saskatchewan, S7N 4H4 Canada.
Li
Fang
F
Gordon
John R
JR
Xiang
Jim
J
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D019744:Chemokines, C; D002631:Chemotactic Factors, Eosinophil / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology; D003131:Combined Modality Therapy; D003602:Cytotoxicity, Immunologic; D005260:Female; D018014:Gene Transfer Techniques; D006183:H-2 Antigens / Q000096:biosynthesis / Q000276:immunology; D000949:Histocompatibility Antigens Class II / Q000096:biosynthesis / Q000276:immunology; D016219:Immunotherapy, Adoptive / Q000379:methods*; D008213:Lymphocyte Activation / Q000276:immunology; D008222:Lymphokines / Q000096:biosynthesis / Q000235:genetics* / Q000276:immunology; D016393:Lymphoma, B-Cell / Q000235:genetics / Q000276:immunology* / Q000628:therapy; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009101:Multiple Myeloma / Q000235:genetics / Q000276:immunology* / Q000628:therapy; D012795:Sialoglycoproteins / Q000096:biosynthesis / Q000235:genetics* / Q000276:immunology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D018417:Th1 Cells / Q000276:immunology; D019076:Transgenes; D014407:Tumor Cells, Cultured
D019744:Chemokines, C; D002631:Chemotactic Factors, Eosinophil; D006183:H-2 Antigens; C024755:H-2K(K) antigen; D000949:Histocompatibility Antigens Class II; D008222:Lymphokines; D012795:Sialoglycoproteins; C486249:Xcl1 protein, mouse; C018997:lymphotactin