Priming of tumor-specific T cells in the draining lymph nodes after immunization with interleukin 2-secreting tumor cells: three consecutive stages may be required for successful tumor vaccination.

Abstract

Although both CD4+ and CD8+ T cells are clearly required to generate long-lasting anti-tumor immunity induced by s.c. vaccination with interleukin 2 (IL-2)-transfected, irradiated M-3 clone murine melanoma cells, some controversy continues about the site and mode of T-cell activation in this system. Macrophages, granulocytes, and natural killer cells infiltrate the vaccination site early after injection into either syngeneic euthymic DBA/2 mice or athymic nude mice and eliminate the inoculum within 48 hr. We could not find T cells at the vaccination site, which argues against the concept that T-cell priming by the IL-2-secreting cancer cells occurs directly at that location. However, reverse transcription-PCR revealed transcripts indicative of T-cell activation and expansion in the draining lymph nodes of mice immunized with the IL-2-secreting vaccine but not in mice vaccinated with untransfected, irradiated M-3 cells. We therefore propose that the antigen-presenting cells, which invade the vaccination site, process tumor-derived antigens and, subsequently, initiate priming of tumor-specific T lymphocytes in lymphoid organs. These findings suggest a three-stage process for the generation of effector T cells after vaccination with IL-2-secreting tumor cells: (i) tumor-antigen uptake and processing at the site of injection by antigen-presenting cells,(ii) migration of antigen-presenting cells into the regional draining lymph nodes, where T-cell priming occurs, and (iii) circulation of activated T cells that either perform or initiate effector mechanisms leading to tumor cell destruction.

Anti-tumour activity against B16-F10 melanoma with a GM-CSF secreting allogeneic tumour cell vaccine

“…The success of allogeneic K1735-M2 vaccine cells is likely to be due to 'cross-priming' tumour antigen presentation whereby antigens on the tumour vaccine cells are released in the vicinity of the vaccination site and then processed and presented to naive T cells by autologous professional APC [5][6][7]25 making any requirement for MHC matching between the vaccine tumour cells and the vaccine recipient unnecessary. Although we do not know the possible cross-reactive antigen(s) being targeted by the immune response, the in vitro T cell work showed that the allogeneic vaccine generated B16-F10 specific CTLs.…”

“…The involvement of both CD4+ve and CD8+ve T cells in mediating the effects of the allogeneic vaccine led us to believe that it operated via the indirect pathway of antigen presentation also known as 'cross-priming' 5,6 which involves the autologous APC. GM-CSF cytokine improves the recruitment and maturation of professional APCs 24 as well as the efficacy of autologous whole cell melanoma vaccines.…”

“…4 The use of allogeneic vaccines would not only overcome these problems, it also has immunological rationale in the body of data illustrating that tumour antigens from tumour vaccine cells are presented to naive T cells by the host's own antigen presenting cells. [5][6][7][8] This phenomenon of 'cross-priming' eliminates the need for MHC matching in the case of allogeneic vaccine strategy. However, this approach demands that the allogeneic tumour cells used as vaccine share some cross-reactive antigens with the autologous tumour.…”

Cell-free tumor antigen peptide-based cancer vaccines

“…Evidence from both bone marrow transplantation experiments (41) and histological investigations (32,42,43) in the murine system suggests the following working hypothesis for the events leading to the generation of cellular antitumor immunity. In the case of cellular cytokine-secreting irradiated vaccines, macrophage-like cells invade the vaccine deposit of irradiated cells and phagocytose the tumor cells within a relatively short period of days.…”

Phase I clinical trial with IL-2-transfected xenogeneic cells administered in subcutaneous metastatic tumours: clinical and immunological findings

“…Various groups have shown that tumour cells transfected to express immunostimulatory cytokines are able to induce immune responses leading to rejection in experimental animal models (Fearon et al, 1990;Schmidt-Wolf and Schmidt Wolf, 1995;. In some cases, vaccination with cytokine-producing tumour cells protected against subsequent challenge with an otherwise lethal dose of wild-type tumour and eliminated pre-existing cancer deposits (Gansbacher et al, 1990;Dranoff et al, 1993;Maass et al, 1995;Zatloukal et al, 1995;Clary et al, 1997). Unfortunately, in man, the development of autologous tumour vaccines has proven to be more complex due to the requirement for establishing tumour cell lines for each patient and the need for efficient ex vivo transfection.…”