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 s ystemic low dose rIL-2 effectively eradicates pulmonary metastases of the murine MCA-105 sarcoma. We described earlier that host CD8(+) T ce lls are critical for tumor eradication and that successful treatment i s associated with production of high levels of IFN-gamma and granulocy te/macrophage (GM)-CSF by donor TIL in vitro. Here, we propose the mec hanism through which adoptively transferred Thy-1.1(+) TIL induce a ho st 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. T hese Thy-1,1(+) cells produced IFN-gamma and GM-CSF in situ. The perce ntage 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 sig nificantly 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 eradicatio n. This response was tumor specific since TIL obtained from MCA-205 di d not induce high levels of IFN-gamma and GM-CSF and did not induce tu mor eradication of MCA-105 tumor. Coinjection of Thy-1.1(+) TIL and an ti-IFN-gamma or anti-GM-CSF mAb significantly inhibited antitumor effi cacy of the TIL + rIL-2 treatment. We conclude that successful adoptiv e immunotherapy in this model is mediated through cytokine production by adoptively transferred TIL that induce a host T cell dependent anti tumor response.