Successful adoptive cellular immunotherapy is dependent on induction of a host immune response triggered by cytokine (IFN-gamma and granulocyte/macrophage colony-stimulating factor) producing donor tumor-infiltrating lymphocytes.
Adoptive immunotherapy with tumor-infiltrating lymphocytes (TIL) and systemic low dose rIL-2 effectively eradicates pulmonary metastases of the murine MCA-105 sarcoma. We described earlier that host CD8+ T cells are critical for tumor eradication and that successful treatment is associated with production of high levels of IFN-gamma and granulocyte/macrophage (GM)-CSF by donor TIL in vitro. Here, we propose the mechanism through which adoptively transferred Thy-1.1+ TIL induce a host antitumor response in congenic Thy-1.2+ tumor-bearing mice. Donor Thy-1.1+ TIL were detected at the tumor site 12 h after transfer. These Thy-1.1+ cells produced IFN-gamma and GM-CSF in situ. The percentage of Thy-1.1+ TIL at the tumor site increased up to 16.4 +/- 4.9% 24 h after transfer but decreased to undetectable levels thereafter. In contrast, the percentages of host cells producing IFN-gamma and GM-CSF continued to increase at the tumor site. These increases were significantly higher in TIL + rIL-2-treated mice compared with untreated mice and rIL-2-treated mice 48 h after TIL transfer. The appearance of IFN-gamma+ and GM-CSF+ cells was followed by a large influx of host CD4+, CD8+, and Thy-1.2+ TIL and eventually by tumor eradication. This response was tumor specific since TIL obtained from MCA-205 did not induce high levels of IFN-gamma and GM-CSF and did not induce tumor eradication of MCA-105 tumor. Coinjection of Thy-1.1+ TIL and anti-IFN-gamma or anti-GM-CSF mAb significantly inhibited antitumor efficacy of the TIL + rIL-2 treatment. We conclude that successful adoptive immunotherapy in this model is mediated through cytokine production by adoptively transferred TIL that induce a host T cell-dependent antitumor response.
Nagoshi
M
M
Department of Surgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
Goedegebuure
P S
PS
Burger
U L
UL
Sadanaga
N
N
Chang
M P
MP
Eberlein
T J
TJ
D019264:Adoptive Transfer; D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D005260:Female; D005434:Flow Cytometry; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000502:physiology*; D007111:Immunity, Cellular; D007167:Immunotherapy / Q000379:methods*; D007371:Interferon-gamma / Q000502:physiology*; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology*; D008748:Methylcholanthrene; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016513:Mice, SCID; D012513:Sarcoma, Experimental / Q000628:therapy*; D016176:T-Lymphocyte Subsets / Q000276:immunology*; D018800:Thy-1 Antigens
D018800:Thy-1 Antigens; D008748:Methylcholanthrene; D007371:Interferon-gamma; D016178:Granulocyte-Macrophage Colony-Stimulating Factor