Immunotherapeutic alteration of tumor-induced suppression of interleukin 2 and 3 production by Propionibacterium acnes vaccination

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Virginia Polytechnic Institute and State University

Previous reports indicate that anti-tumor activity arising from systemically injected P. acnes is macrophage-mediated, whereas anti-tumor activity arising from locally injected P. acnes is T cell-mediated. It is possible these P. acnes-induced cytotoxic T cells arise via the Interleukin cascade. Therefore, this study investigated the involvement of Interleukin 2 (IL 2) and Interleukin 3 (IL 3), known components of the Interleukin cascade, in local P. acnes-mediated anti-tumor action.

A 500 ug dose of heat-killed stationary phase P. acnes given simultaneously with 10⁴ tumor cells was found to inhibit tumor formation completely, therefore this amount was used as a standard dose throughout the study. Unvaccinated counterparts developed palpable tumors two weeks after tumor cell administration. Lower doses of vaccine protected animals from tumor growth to a lesser degree. A vaccine prepared from logarithmic phase P. acnes exerted a moderate anti-tumor effect in some cases.

IL 2 and IL 3 levels were measured in vitro in normal BALB/c mice (N), tumor-bearing mice (TBH), normal vaccinated mice (N+V), and mice receiving both tumor cell and vaccine injection (T+V). IL 2 and IL 3 production was maintained in both N and N+V host splenocyte cultures throughout the study. In a similar fashion, levels of IL 2 and IL 3 in T+V host splenocyte cultures were comparable to those of N+V hosts. However, TBH splenocyte production of IL 2 and IL 3 began to decline when tumors became palpable, at Day 14 after tumor cell inoculation. By Day 28, TBH IL 2 and IL 3 levels were <15% of normal control levels.

Causes for this suppression of IL 2 and IL 3 production in TBH were examined. From reports of others it appeared that suppression may be mediated through prostaglandin(s). Addition of the prostaglandin inhibitor indomethacin to splenocyte cultures greatly enhanced IL 2 production by N, N+V and T+V splenocytes, but failed to restore IL 2 production in TBH splenocyte cultures to normal levels. Thus, it appeared prostaglandins were not directly responsible for the majority of suppression seen in TBH. In the non-tumor-burdened host, prostaglandin appeared to play a homeostatic role regarding IL 2 production. Indomethacin-treatment had little effect on IL 3 production.

Nylon wool fractionation of N, TBH, N+V and T+V splenocytes suggested a cell removed by nylon wool treatment was largely responsible for the suppression of IL 2 and IL 3 production in TBH. No obvious presence of functional suppressor cells was noted in N, N+V or T+V splenocytes.

From these results, it appeared that P. acnes administration maintains and/or restores IL 2 and IL 3 production, thus favoring the production of CTL. In addition, the suppression of IL 2 and IL 3 production seen in TBH may be due to a nylon wool adherent suppressor cell. A model describing the effect of P. acnes administration on local anti-tumor activity was presented.