Interleukin-12 requires initial CD80-mediated T-cell activation to support immune responses toward human breast and ovarian carcinoma

Abstract

One possible reason for the poor immunogenicity of tumors is the induction of peripheral tolerance by tumor cells that fail to deliver costimulatory signals. Furthermore, T cells stimulated with wild-type tumor cells often fail to secrete cytokines. The present study has been undertaken to identify cytokines that cooperate with CD80 in T-cell activation in vitro toward human breast and ovarian carcinoma cell lines. Tumor cell-mediated T-lymphocyte activation was analyzed directly in allogeneic mixed lymphocyte/tumor cell cultures as proliferation and effector functions were assessed in cytotoxic T-cell assays. Interleukin-7 (IL-7) amplified the proliferative response toward CD80-transfected breast and ovarian carcinomas and stimulated predominantly CD4 ϩ T lymphocytes. IL-12 represses the proliferative response of naive T cells but cooperates with CD80-mediated activation during secondary stimulations. In long-term T-cell cultures, IL-12 synergizes with CD80 expression to stimulate cytolytic CD8 ϩ T-cell lines, which recognize a breast carcinoma line in a human histocompatibility leukocyte antigen-restricted manner. These studies illustrate that costimulation is necessary for tumor cells to function as alloantigen-presenting cells. Furthermore, when added after the priming of T cells with CD80-transfected tumor cells, IL-12 could be helpful in propagating sufficient T-cell numbers to be used in adoptive transfers during cellular immunotherapy.

Enhanced Antitumor Effect of Oncolytic Adenovirus Expressing Interleukin-12 and B7-1 in an Immunocompetent Murine Model

“…It has also been shown that B7-1-expressing tumor vaccines have been implicated to elicit CD8 + CTLs directly (15). Interestingly, Guckel et al (16) reported that expression of IL-12 results in improvement in generating tumor-reactive T cells. Further, Kubin et al (17) showed that IL-12 expression leads to a synergistic antitumor effect with a helper T (Th1) pattern cytokine production.…”

Phase I Study of the Intratumoral Administration of Recombinant Canarypox Viruses Expressing B7.1 and Interleukin 12 in Patients with Metastatic Melanoma

“…IL-12 was shown to increase in vitro lymphoproliferative responses versus autologous melanoma tumors transfected with B7.1 (16). In addition, it has been shown that IL-12 required initial B7.1-mediated T-cell activation to support immune responses toward human breast and ovarian carcinoma in vitro (17). The intratumoral injection of adenovirus-mediated coexpression of B7.1 and IL-12 effectively elicited antitumor immunity in a nonimmunogenic, therapy-resistant, mouse pancreatic cancer model (18).…”

Therapeutic Vaccination in Chronic Hepatitis B: Preclinical Studies in the Woodchuck

“…In the study, large (2-5 cm) intrahepatic tumors of 5 woodchucks were injected with a single dose of 1 × 10 9 PFU AdV expressing IL-12 and B7.1 molecule (AdIL-12/B7.1). The B7.1 molecule (also known as a CD80) is naturally expressed on the professional APCs and provides the synergistic effect in the tumor regression [181,186,187]. In 4 out of 5 animals, AdIL-12/B7.1 was delivered by laparotomy into the three HCC nodules and three nodules were injected with a vector expressing GFP as a control.…”