GENE-MODIFIED TUMOR VACCINE WITH THERAPEUTIC POTENTIAL SHIFTS TUMOR-SPECIFIC T-CELL RESPONSE FROM A TYPE-2 TO A TYPE-1 CYTOKINE PROFILE

Vaccination with a poorly immunogenic/nonimmunogenic tumor fails to pr otect the host from a subsequent challenge with the same tumor, The me chanisms underlying the failure of these tumors to sensitize therapeut ic T cells are not clearly understood, but the inability of host T cel ls to recognize tumor has been implicated. In this study, vaccination with the poorly immunogenic B16BL6-D5 (D5 H-2(b)) tumor fails to gener ate therapeutic T cells from the tumor vaccine-draining lymph nodes (T VDLN) in our adoptive immunotherapy model. However, if vaccination is performed with an allogeneic MHC class I gene (H-2 K-d)-modified tumor , the T cells obtained from the TVDLN are therapeutic after activation with anti-CD3 and IL-2. Lymph nodes (LN) draining both D5 and D5-K-d tumor vaccines contained increased numbers of cells with reduced expre ssion of L-selectin (L-selectin(low/-)) compared with naive LN. This i mplies that vaccination led to sensitization of T cells even in LN dra ining the unmodified D5 tumor, L-selectin(low/-) cells from D5-K-d, bu t not D5, TVDLN were therapeutic in our animal model. No antitumor act ivity was seen in the high level L-selectin T cells, L-selectin(low/-) T cells exhibited tumor-specific cytokine release that was type 2 (IL -4, IL-10) following vaccination with native D5 and type 1 (IFN-gamma) following vaccination with gene-modified D5.K-d. Our data suggest tha t the failure of unmodified D5 to generate therapeutic T cells is not due to an inability to recognize tumor Ags, but, rather, to the induct ion of an immune response that is;ineffective in mediating tumor regre ssion, i.e., immune deviation.