Amplification of tumor immunity by gene transfer of the co-stimulatory 4-1BB ligand: synergy with the CD28 co-stimulatory pathway

Abstract

We have explored the role of an activation-induced T cell molecule, 4-1BB (CDw137), in the amplification of tumor immunity by retrovirus-mediated transduction of the 4-1BB ligand (4-1BBL) into tumor cells. Mice inoculated with P815 tumor cells expressing 4-1BBL developed a strong cytotoxic T lymphocyte (CTL) response and long-term immunity against wild-type tumor. The optimal effect of 4-1BBL in CTL stimulation required B7-CD28 interaction since blockade of this interaction by antibodies down-regulated the expression of 4-1BB on T cells and decreased CTL activity. Furthermore, co-expression of 4-1BBL and B7-1 in the poorly immunogenic AG104A sarcoma enhanced the induction of effector CTL and the rejection of the wild-type tumor while neither 4-1BBL nor B7-1 single transfectants were effective, suggesting a synergistic effect between the 4-1BB and the CD28 co-stimulatory pathways. Our results underscore the importance of the 4-1BB T cell stimulation pathway in the amplification of an antitumor immune response.

Role of 4-1BB:4-1BB ligand in cancer immunotherapy

“…In the murine sarcoma cell line Ag104, the tumor cells which express 4-1BBL had no therapeutic activity unless they were also transfected with B7-1. 78 However, the injection of a-4-1BB Ab into mice with the same tumor (Ag104) caused tumor destruction. 47 In addition mAb against the T-cell activation molecule 4-1BB was effective in the treatment of established mouse tumors.…”

“…The optimal effect of 4-1BBL in CTL stimulation required B7-CD28 signaling since Ab blockade of this downregulated the expression of 4-1BB on T cells and decreased CTL activity. 78 In studies using the A20, B-cell lymphoma cell line, 81 mice injected with tumors expressing the vector backbone alone (A20/CMV) or B7-1 (A20/B7-1) developed tumors within 25 days of subcutaneous injection. In contrast, mice injected with A20/4-1BBL were tumor free for the 150-day follow-up period, and few (25%) of the mice injected with A20/B7-2 developed tumors.…”

“…To date only a small number of studies have directly compared the costimulatory molecules within a single tumor model system. 78,81 These studies have shown that transfection of 4-1BBL cDNA into a tumor cell which had innate B7-1 and B7-2 expression could create a whole cell tumor vaccine which was more efficacious than transfection of the same cells with either B7-1 or B7-2 alone.…”

“…81 Coexpression of 4-1BBL and B7-1 in the poorly immunogenic AG104A sarcoma enhanced the induction of effector CD8 þ T cells which could reject even the poorly immunogenic wild-type AG104A tumor while neither 4-1BBL nor B7-1 single transfectants were as effective. 78 NRS1 was a murine squamous cell carcinoma that constitutively expresses B7-1 at high levels, yet it was the introduction of the 4-1BBL cDNA that efficiently elicited antitumor immune responses in syngeneic mice which then acquired specific immunity against the wild-type tumor. 82 Guinn et al 61 showed that in a A20 model in mouse, protective immunity against parental tumors involved both the 4-1BBL and CD28 pathways.…”

“…B7/CD28 pathway does not always protect the host against wild-type tumor but the B7/CD28 pathway was required for the optimal effect of 4-1BB:4-1BBL. 78 The level of 4-1BBL expression on modified tumor cells also appears to be important. Higher levels of the costimulatory molecules appeared to be more effective in inducing antitumor responses.…”