Targeting the primary tumor to generate CTL for the effective eradication of spontaneous metastases.
Metastatic disease is the major cause of morbidity and mortality in cancer. Although surgery, chemotherapy, or radiation can often control primary tumor growth, successful eradication of disseminated metastases remains rare. We have now tested whether direct targeting tumor tissues to generate antitumor immune response before surgical excision produces sufficient CTL against micrometastases. One unsolved problem is whether such response allows coming CTL to be educated and then exit the tumor site. Another unsolved problem is whether these CTL can then patrol and effectively eliminate spontaneously metastasized tumor cells in the periphery. In this study, we have shown that adenovirus-expressing TNFSF14 [LIGHT (name derived from homologous to lymphotoxins, shows inducible expression, and competes with herpes simplex virus glycoprotein D for herpes virus entry mediator, a receptor expressed by T lymphocytes); Ad-LIGHT] inoculated directly into primary 4T1 tumor, a highly aggressive, spontaneously metastasizing mammary carcinoma, followed by surgical removal of the primary tumor can eradicate established and disseminated metastatic tumor cells in the peripheral tissues. Furthermore, we clearly show with a fibrosarcoma model Ag104L(d) that local treatment can generate plenty of tumor-specific CTL that exit the primary tumor and infiltrate distal tumors to completely eradicate distal tumors. Therefore, targeting the primary tumor with Ad-LIGHT before surgical excision is a new strategy to elicit better immune response for the eradication of spontaneous metastases.
Yu
Ping
P
Committee on Immunology and Department of Pathology, University of Chicago, Chicago, IL 60637, USA. pingyu@uchicago.edu
Lee
Youjin
Y
Wang
Yang
Y
Liu
Xiaojuan
X
Auh
Sogyong
S
Gajewski
Thomas F
TF
Schreiber
Hans
H
You
Zhaoyang
Z
Kaynor
Campbell
C
Wang
Xinzhong
X
Fu
Yang-Xin
YX
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D000951:Antigens, Neoplasm / Q000276:immunology; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000276:immunology / Q000473:pathology / Q000517:prevention & control; D003602:Cytotoxicity, Immunologic / Q000235:genetics; D005260:Female; D005822:Genetic Vectors / Q000502:physiology; D006084:Graft Rejection / Q000235:genetics / Q000276:immunology; D006801:Humans; D007113:Immunity, Innate / Q000235:genetics; D008175:Lung Neoplasms / Q000276:immunology* / Q000517:prevention & control / Q000556:secondary*; D008213:Lymphocyte Activation / Q000235:genetics / Q000276:immunology; D008325:Mammary Neoplasms, Experimental / Q000276:immunology* / Q000473:pathology / Q000628:therapy*; D008546:Melanoma, Experimental / Q000276:immunology / Q000473:pathology / Q000517:prevention & control; D051379:Mice; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D013601:T-Lymphocytes / Q000276:immunology / Q000473:pathology; D013602:T-Lymphocytes, Cytotoxic / Q000166:cytology / Q000276:immunology*; D053326:Tumor Necrosis Factor Ligand Superfamily Member 14 / Q000235:genetics / Q000502:physiology
D000951:Antigens, Neoplasm; D053326:Tumor Necrosis Factor Ligand Superfamily Member 14