Therapy of disseminated murine leukemia with cyclophosphamide and immune Lyt-1+,2- T cells. Tumor eradication does not require participation of cytotoxic T cells.

Abstract

Animal models have been developed (1-4) in which established and disseminated tumors can be eradicated by the adoptive transfer of syngeneic T cells specifically immune to tumor-associated antigens. These models have served as prototypes for understanding how the immune system of a tumor-bearing host might be manipulated to promote in vivo lysis of advanced tumors. Many factors necessary for successful immunotherapy have now been elucidated, including the need for immune effector T cells capable of persisting in the host (5, 6), the long time period required for elimination of all tumor cells by immune cells in vivo (5), and the importance of ablating suppressor cells, induced in the host by the growing tumor, which interfere with the expression of transferred immunity (3, 7). Although specific T cell immunity is necessary for tumor eradication, it has been difficult to determine which immunologic effector mechanism(s) must be operative in vivo for these transferred T cells to be effective.Cytolytic T cells (CTL) ~ can directly and immediately kill tumor cells in vitro. Adoptively transferred CTL have been shown to prevent the outgrowth of recently transplanted tumors, and to contribute to tumor elimination in some therapy settings (4,8,9); the rejection of a murine sarcoma following transfer of immune T cells has been correlated with the in vivo generation of CTL (10). Thus, CTL may be important for the elimination of established disseminated tumors. However, studies using purified functional subsets of immune T cells have suggested that transfer of the noncytolytic helper T cell subset, which presumably can induce a tumoricidal delayed-type hypersensitivity (DTH) response in vivo, is necessary and sufficient for tumor eradication (11,12). This conclusion was supported by studies (13) suggesting that a similar DTH phenom-

Ex vivo priming of CD4 T cells converts immunological tolerance into effective antitumor immunity in a murine model of acute lymphoblastic leukemia

“…44 Analysis of the participation of distinct T-cell populations in elimination of Friend murine leukemia virusinduced tumor FBL-3 showed that tumor-specific CD4 T cells in combination with cyclophosphamide can exert their effect independently of CD8 T cells. 33 Thus, our investigations extend previously published concepts and point to a specific priming deficiency of anti-leukemia CD4 T cells affecting proper tumor surveillance, whereas the role of CD8 T cells in CD4 T cell-based adoptive immunotherapy remains to be investigated.…”

“…47 We here provide evidence that IFN-producing CD4 T cells represent critical players in anti-leukemia immunity, supporting previously published evidences. 22,23,33,47 In a solid tumor model, Mumberg et al 22 have previously shown that antitumor effects of adoptively transferred CD4 T cells depend on IFN-g. In contrast to our model, these authors used a fibrosarcoma system subcutaneously injected into SCID mice that could be rejected independently of CD8 T cells.…”

“…Previous studies in various solid tumor models suggested that CD4 T cell help is needed for efficient CD8-mediated tumor destruction. 32 Various investigators addressed this issue by experiments using adoptive transfer [33][34][35] or depletion of CD4 T cells [36][37][38] to substantiate the role for CD4 mediated antitumor immunity. Mechanistically, the role of CD4 T cells is still not completely understood.…”

CD4+, IL17 and Foxp3 Expression in Different pTNM Stages of Operable Non-small Cell Lung Cancer and Effects on Disease Prognosis

“…This characteristic enables the alien cells to be recognized only by CD8 + T cells, and not by CD4 + T cells. However, it is found that CD4 + T cells can reversely induce antigenpresenting cells (APC) to supply CD8+T cells and other immune cell costimulatory molecules (Greenberg et al, 1985). Though there is only low level of MHC class II antigen express in entitative tumor cells, the IFN γ stimulation can upregulate the expression of MHC class II antigen.…”

Th1 and Th2 Cell Clones to a Poorly Immunogenic Tumor Antigen Initiate CD8+ T Cell-Dependent Tumor Eradication In Vivo

“…Independent of the cytokine secretion profiles, the adoptive transfer of CD4 ϩ cells has also been reported to eradicate established tumors in a variety of experimental models (35)(36)(37). In most of these systems, the therapeutic activity of CD4 ϩ T cells was traced to activation of NK or macrophage effector cells or to direct lysis of class II-expressing tumor cells.…”