Synergy between interleukin-2 and prothymosin alpha for the increased generation of cytotoxic T lymphocytes against autologous human carcinomas

Peripheral blood mononuclear cells (PBMC) from cancer patients were culture d in vitro with irradiated autologous tumor cells isolated from malignant e ffusions (mixed lymphocyte tumor cultures, MLTC) and low-dose (50 IU/ml) re combinant interleukin-2 (IL-2). The combination of IL-2 and prothymosin alp ha (ProT alpha) resulted in a greater PBMC-induced response to the autologo us tumor than that brought about by IL-2 alone. In particular, ProT alpha s pecifically enhanced the CD4(+) T-cell-mediated proliferation against the a utologous tumor. CD4(+) T cells seemed to recognize tumor antigens presente d by HLA-DR molecules expressed on the autologous monocytes, since preincub ation of the latter with an anti-HLA-DR monoclonal antibody (mAb) abrogated the response. In addition, MLTC set up with IL-2 and ProT alpha also gener ated more MHC-class-I-restricted cytotoxic T lymphocytes (CTL) against; the autologous tumor than did MLTC set up with IL-2 alone. The MLTC-induced CT L contained high levels of cytoplasmic perforin and their development was s trictly dependent on the presence of both autologous CD4(+) T cells and mon ocytes. In the absence of either population there was a strong impairment o f both proliferative and cytotoxic responses which was not restored by the presence of ProT alpha. In contrast, when both cell populations were presen t, ProT alpha exerted optimal enhancement of CD4(+) T cell proliferation, w hich was associated with potentiated CTL responses. Our data emphasize the role of ProT alpha for the enhancement of IL-2-induced CTL responses agains t autologous tumor cells. Such responses require collaborative interactions between CD4(+), CD8(+) T cells and monocytes as antigen-presenting cells. Our data are relevant for adoptive immunotherapeutic settings utilizing IL- 2 and ProT alpha-induced autologous-tumor-specific CTL.