Induction of an antitumour adaptive immune response elicited by tumour cells expressing de novo B7‐1 mainly depends on the anatomical site of their delivery: the dose applied regulates the expansion of the response

Abstract

Summary De novo expression of costimulatory molecules in tumours generally increases their immunogenicity, but does not always induce a protective response against the parental tumour. This issue was addressed in the mouse Sp6 hybridoma model, comparing different immunization routes (subcutaneous, intraperitoneal and intravenous) and doses (0·5 × 106 and 5 × 106 cells) of Sp6 cells expressing de novo B7‐1 (Sp6/B7). The results can be summarized as follows. First, de novo expression of B7‐1 rendered Sp6 immunogenic, as it significantly reduced the tumour incidence to ≤15% with all delivery routes and doses tested, whereas wild‐type Sp6 was invariably tumorigenic (100% tumour incidence). Second, long‐lasting protection against wild‐type Sp6 was mainly achieved when immunization with Sp6/B7 was subcutaneous: a dose of 0·5 × 106 Sp6/B7 cells elicited protection that was confined to sites in the same anatomical quarter as the immunizing injection. Repeated injections of the same dose extended protection against wild‐type Sp6 to other anatomical districts, as well as a single injection of a 10‐fold higher dose (5 × 106 cells). Finally, Sp6‐specific cytotoxic T‐lymphocyte activity was detected in draining lymph nodes, and the splenic expansion of Sp6‐specific cytotoxic T‐lymphocyte precursors quantitatively correlated with the dose of antigen. We conclude that activation of a protective immune response against Sp6 depends on the local environment where the immunogenic form of the ‘whole tumour cell antigen’ is delivered. The antigen dose regulates the anatomical extent of the protective response.

Immune Regulation by Mesenchymal Stem Cells Derived from Adult Spleen and Thymus

“…Sp6 cells, injected s.c. alone or mixed with 0.5 ϫ 10 6 BM-, spleen-, or thymus-derived MSCs, in the same anatomical quarter of immunizing injection (usually within a radius of 0.5 cm around the first Sp6/B7 inoculum), as previously described (39).…”

“…Sp6, thus making mice refractory to w.t. Sp6 tumor development (39). We used this mouse model to study the specific anti-tumor immunity in vitro and in vivo in the presence or absence of BM-, spleen-, and thymus-derived MSCs as third party.…”

“…Sp6 target cells, as assessed by standard 51 Cr release assays, using spleen effector cells derived from immunized mice (39). As shown in Fig.…”

“…To this aim, we have collected, expanded and characterized human and mouse, spleen-and thymus-derived adherent stromal cells by using the same procedures currently used to obtain MSCs from BM. Then, we have assessed the in vitro immunoregulatory potential of these adherent cells co-cultured with different immune effector cells, and, finally, we have tried to clarify the kinetics of their in vivo inhibitory effect during the development of a tumor-specific immune response, in a plasmacytoma-derived mouse tumor model (39).…”

Antitumor activity of the intratumoral injection of fowlpox vectors expressing a triad of costimulatory molecules and granulocyte/macrophage colony stimulating factor in mesothelioma

“…[27][28][29] Transduction of tumor cells with a costimulatory molecule, such as B7-1, can provide signals necessary for effective T cell activation that are not provided by tumors, as well as activate other immune effector mechanisms in situ and in draining lymph nodes. 30 Transduction of tumor cells with B7-1, however, has not been uniformly effective. 31 Furthermore, transduction of B7-1 but not of B7-2 was effective in previous studies of mesothelioma.…”