Synergistic effect of adoptive T-cell therapy and intratumoral interferon gamma-inducible protein-10 transgene expression in treatment of established tumors.
The lack of efficient T-cell infiltration of tumors is a major obstacle to successful adoptive T-cell therapy. We have previously shown that transplanted SP2/0 myeloma tumors engineered to express lymphotactin invariably induced tumor regress mediated by SP2/0 tumor-specific T cells. Herein, we further systemically characterize these activated T cells and investigate their therapeutic efficacy, either alone or with the chemokine interferon gamma (IFN-gamma)-inducible protein-10 (IP-10) gene therapy. Following stimulation with SP2/0 cells, these activated T cells were CD25(+)FasL(+) L-selectin(low), expressed CXCR3 receptor and were chemoattracted by IP-10 in vitro. They comprised 64% CD4(+) Th1 and 36% CD8(+) Tc1 cells, both of which expressed IFN-gamma, perforin, and TNF-alpha, but not IL-4. The activated T cells were strongly cytotoxic for SP2/0 tumor cells (79% specific killing; E:T ratio, 50), mainly via perforin-mediated pathway. Cell tracking using labeled T cells confirmed that these T cells infiltrated better into the IP-10-expressing tumors than non-IP-10-expressing ones. In vivo, combined intratumoral IP-10 gene transfer and adoptive T-cell immunotherapy for well-established SP2/0 tumors eradicated the tumors in 7 of the 8 mice. Control or IP-10 adenoviral treatments by themselves neither 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. Taken together, our data provide solid evidence of a potent synergy between adoptive T-cell therapy and IP-10 gene transfer into tumor tissues, which culminated in the eradication of well-established tumor masses.
Huang
Hui
H
Research Unit, Saskatchewan Cancer Agency, Department of Microbiology, University of Saskatchewan, Saskatoon, Saskatchewan, Canada S7N 4H4.
Liu
YongQing
Y
Xiang
Jim
J
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D002465:Cell Movement; D002478:Cells, Cultured; D054357:Chemokine CXCL10; D019744:Chemokines, C; D019743:Chemokines, CXC / Q000235:genetics* / Q000378:metabolism; D003131:Combined Modality Therapy; D015316:Genetic Therapy; D005822:Genetic Vectors; D016219:Immunotherapy, Adoptive; D008213:Lymphocyte Activation; D008222:Lymphokines / Q000235:genetics; D051379:Mice; D008807:Mice, Inbred BALB C; D009101:Multiple Myeloma / Q000276:immunology / Q000473:pathology / Q000628:therapy; D009368:Neoplasm Transplantation; D009374:Neoplasms, Experimental / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D009389:Neovascularization, Pathologic; D012795:Sialoglycoproteins / Q000235:genetics; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology / Q000637:transplantation*; D018417:Th1 Cells / Q000276:immunology; D019076:Transgenes; D014407:Tumor Cells, Cultured
D054357:Chemokine CXCL10; D019744:Chemokines, C; D019743:Chemokines, CXC; D008222:Lymphokines; D012795:Sialoglycoproteins; C486249:Xcl1 protein, mouse; C018997:lymphotactin