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T cell-mediated tumor rejection displays diverse dependence upon perforin and IFN-gamma mechanisms that cannot be
L Peng1, J C Krauss, G E Plautz
1Center for Surgery Research, Cleveland Clinic Foundation, Cleveland, OH 44195, USA. pengl@ccf.org
Abstract:
Experimental pulmonary metastases have been successfully treated by adoptive transfer of tumor-sensitized T cells from perforin knockout (KO) or Fas/APO-1 ligand(KO) mice, suggesting a prominent role for secretion of cytokines such as IFN-gamma. In the present study we confirmed that rejection of established methylcholanthrene-205 (MCA-205) pulmonary metastases displayed a requirement for T cell IFN-gamma expression. However, this requirement could be obviated by transferring larger numbers of tumor-sensitized IFN-gamma (KO) T cells or by immunosensitizing sublethal irradiation (500 rad) of the host before adoptive therapy. Extrapulmonary tumors (MCA-205 s.c. and intracranial) that required adjunct sublethal irradiation for treatment efficacy also displayed no requirement for host or T cell expression of IFN-gamma. Nonetheless, rejection of MCA-205 s.c. tumors and i.p. EL-4 tumors, but not MCA-205 pulmonary or intracranial tumors, displayed a significant requirement for T cell perforin expression (i.e., CTL participation). The capacity of T cells to lyse tumor targets and secrete IFN-gamma in vitro before adoptive transfer was nonpredictive of the roles of these activities in subsequent tumor rejection. Adoptive therapy studies employing KO mice are therefore indispensable for revealing a diversity of tumor rejection mechanisms that may lack in vitro correlation due to delays in their induction. Seemingly contradictory KO data from different studies are reconciled by the capacity of anti-tumor T cells to rely on alternative mechanisms when treated in larger numbers, the variable participation of CTL at different anatomic locations of tumor, and the apparent capacity of sublethal irradiation to provide a therapeutic alternative to host or T cell IFN-gamma production.
Insights
Tumor rejection via adoptive T cell therapy depends on various mechanisms, including IFN-gamma and perforin, which can be influenced by cell numbers and tumor location. Sublethal irradiation offers an alternative therapeutic approach.
Area of Science:
- Immunology
- Cancer Research
- Cellular Therapy
Background:
- Adoptive T cell transfer is a promising cancer immunotherapy strategy.
- Previous studies suggested a critical role for T cell-derived IFN-gamma (Interferon-gamma) and perforin in rejecting experimental pulmonary metastases.
Purpose of the Study:
- To investigate the precise mechanisms of tumor rejection mediated by adoptive T cell transfer.
- To determine the roles of T cell IFN-gamma and perforin in rejecting tumors at different anatomical sites.
- To explore factors that can overcome the limitations of T cell-mediated tumor rejection.
Main Methods:
- Utilized adoptive transfer of tumor-sensitized T cells from knockout (KO) mice lacking perforin or Fas/APO-1 ligand.
- Administered T cells to hosts with established methylcholanthrene-205 (MCA-205) pulmonary metastases, subcutaneous (s.c.) tumors, and intracranial tumors.
- Investigated the effect of increasing T cell numbers and employing sublethal irradiation (500 rad) on therapeutic efficacy.
Main Results:
- Rejection of established pulmonary metastases required T cell IFN-gamma, but this could be bypassed by using higher numbers of IFN-gamma KO T cells or by host irradiation.
- Extrapulmonary tumors (s.c. and intracranial) treated with irradiation showed no requirement for host or T cell IFN-gamma.
- Rejection of s.c. and intraperitoneal tumors, but not pulmonary or intracranial tumors, required T cell perforin (cytotoxic T lymphocyte participation).
Conclusions:
- Tumor rejection mechanisms are diverse and context-dependent, varying with tumor location and the number of adoptively transferred T cells.
- In vitro T cell functions (lysis, IFN-gamma secretion) do not always predict in vivo therapeutic efficacy.
- Sublethal irradiation can serve as an alternative strategy to IFN-gamma production for effective tumor rejection, highlighting the adaptability of anti-tumor T cell responses.
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