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摘要
T lymphocytes immune to tumor-associated antigens (TAA) on syngeneic tumor cells can readily be shown to lyse tumor cells in vitro and inhibit the growth of transplanted tumors if administered shortly before, with or, shortly after the inoculation of tumor. However, after a tumor has become established in the host, therapy with adoptively transferred lymphocytes alone has generally been ineffective (1). The limited ability of adoptive immunotherapy to eradicate established tumors presumably reflects consequences of a growing tumor, such as a large tumor burden and induction of suppressor cells or suppressor factors in the host (2, 3). Thus, immunotherapeutic approaches that include modifying this underlying host-tumor relationship have been more successful. For example, in therapy of established locally growing rat and murine fibrosarcomas, the efficacy of immune T cells in enhanced if, before inoculation of the tumors, the host has been irradiated or rendered T cell deficient (3, 4). Several immunotherapy models have been developed in our laboratory in which mice with established disseminated syngeneic leukemias can be effectively treated with a combination of noncurative, nonlethal chemotherapy with cyclophosphamide (CY),(1) followed by adoptively transferred syngeneic immune cells (5-8). In these models, the CY has a direct tumoricidal effect (6), as well as potentially facilitating effects on host tumor immunity, and therapy with immune cells without CY has no apparent in vivo anti-tumor effect (5). In vivo efficacy in such adoptive chemoimmunotherapy (ACIT) requires immune T cells capable of proliferating in the host after adoptive transfer (5, 7), and studies of ACIT of two non-cross-reactive tumors of C57BL/6 origin have confirmed that the lymphocytes must be specifically immune to the relevant tumor (8).
The cellular mechanisms by which adoptively transferred T cells mediate tumor destruction in vivo might be further elucidated by determination of the functional T cell subsets operative in immunotherapy. Although the end results might reflect direct tumor lysis by infused cytotoxic donor cells, comparisons of the ability of immune lymphocytes to mediate in vitro tumor lysis and in vivo immunotherapy have generally revealed a poor correlation between these two effector functions (4, 9, 10). Expression of Lyt antigens has been shown to be useful for separating functional T cell subsets (reviewed in 11, 12). By negative selection using cytotoxic depletion with antibody and complement, T cells can be operationally separated into Lyt-1(+)2(-) cells containing the amplifier, helper, and delayed type hypersensitivity (DTH) effector cells, Lyt-1(-)2(+) cells containing cytotoxic and suppressor cells, and an Lyt-1(+)2(+) compartment containing precursors for the other T cell subsets, as well as portion of cytotoxic and suppressor effector cells (11, 12). In particular, cytotoxic T lymphocytes (CTL) to syngeneic tumors appear to reside in both the Lyt-1(-)2(+) and Lyt-1(+)2(+) compartments (13-17). Therefore, in the present studies, the efficacy of T cell subpopulations, as distinguished by expression of Lyt antigens, was analyzed in ACIT of established murine leukemia and in in vitro assays for the generation and expression of cytotoxicity. The results demonstrate that the phenotype of the predominant T cell subset required for efficacy in ACIT is Lyt-1(+)2(-), which is distinct from the T cell phenotypes mediating in vitro tumor lysis.
- 出版日期2013-3-1
