IMMUNE RESPONSIVENESS TO A MURINE MAMMARY-CARCINOMA MODIFIED TO EXPRESS B7-1, INTERLEUKIN-12, OR GM-CSF

This report characterizes the immunological host response to a syngene ic murine mammary carcinoma along with variants genetically modified t o express B7-1 or secrete GM-CSF and interleukin-12 (IL-12). MT-901 is a subline of a mammary adenocarcinoma that was chemically induced in the Balb/c host. It was found to be weakly immunogenic by immunization /challenge experiments, and it induced tumor-specific T-cell responses in lymph nodes (LN) draining progressive subcutaneous tumors. Tumor c lones expressing B7-1 or secreting GM-CSF exhibited reduced tumorigeni city without completely abrogating tumor growth, whereas IL-12 elabora tion lead to complete tumor growth inhibition. In vivo subcutaneous in oculation of a transgenic cell clone secreting GM-CSF (240 ng/10(6) ce lls/24 hours) resulted in significantly enhanced T-cell reactivity of tumor-draining lymph node (TDLN) cells as compared to wild-type TDLN c ells. This finding was obtained from observations assessed by several different methods, including: 1) in vitro cytotoxicity, 2) in vitro in terferon-gamma release, and 3) adoptive transfer in mice with establis hed tumor. Moreover, the transfer of activated LN cells derived from m ice inoculated with GM-CSF-secreting tumor cells resulted in the prolo nged survival of animals with macroscopic metastatic disease, which wa s not evident utilizing LN cells from mice inoculated with wild-type t umor. By contrast, clones that expressed B7-1 or IL-12 (4 ng/10(6) cel ls/24 hours) did not elicit enhanced tumor-reactive TDLN cells compare d with wild-type tumor when assessed in the adoptive transfer model. T he autocrine secretion of GM-CSF by transduced tumor cells was found t o serve as an effective immune adjuvant in the host response to this w eakly immunogenic tumor.