Transforming Growth Factor‐β CD4+ T cells Tumor‐bearing state Immunosuppression Enhanced Production of TGF‐β and a Progressive Increase in TGF‐β Susceptibility of Anti‐tumor CD4+ T Cell Function

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Abstract
The present study deals with the effect of transforming growth factor‐β (TGF‐β) on anti‐tumor immune responsiveness at various stages of the tumor‐bearing state. Spleen cells from BALB/c mice bearing a syngeneic tumor (CSA1M) 1–3 wk after inoculation with CSA1M cells produced interleukin‐2 (IL‐2) and macrophage‐activating factor (MAF)/interferon‐γ (IFN‐γ) upon in vitro culture without addition of exogenous tumor antigens. This lymphokine production was achieved through collaboration between anti‐CSA1M CD4+ T cells and antigen‐presenting cells that had been pulsed with CSA1M tumor antigens in vivo in the tumor‐bearing state. The IL‐2‐producing capacity of CD4+ T cells reached the maximal level as early as one week after tumor implantation but decreased with the progress of tumor‐bearing stages. In contrast, the capacity of CD4+ T cells to produce MAF/IFN‐γ was not affected but was maintained at high levels even late in the tumor‐bearing state. The addition of recombinant TGF‐β (rTGF‐β) to cultures of spleen cells from various tumor‐bearing stages resulted in the suppression of lymphokine production. However, the magnitude of the TGF‐β‐induced suppression varied depending on which tumor‐bearing stages of splenic cells were tested as a responding cell population; it was slight in cells from early (1–3 wk) tumor‐bearing stages but increased in cells from donor mice at later tumor‐bearing stages. Thus, spleen cells from late tumor‐bearing stages with weak but significant IL‐2‐producing and considerable MAF/IFN‐γ producing capacities failed to produce these lymphokines when rTGF‐β was present in cultures. A progressive increase in the TGF‐β susceptibility was also observed for IL‐4‐producing Th2 as well as IL‐2/MAF‐producing Th1 cells. In addition, increased levels of TGF‐β were detected in plasma from tumor‐bearing mice at late stages. Taken together, these results indicate that tumor‐bearing mice exhibit enhanced production of TGF‐β as well as a progressive increase in the susceptibility of anti‐tumor CD4+ T cells to TGF‐β‐induced suppressive mechanisms.