Urinary neopterin does not reflect the local antitumor immune milieu in ovarian cancer

Abstract

The main objective of the present investigation was to study the urinary neopterin excretion in the context of the activation of the adaptive cellular immune system at the tumor site. For this purpose, we compared pre-treatment urinary neopterin levels measured in 92 ovarian cancer patients, with intratumoral levels of mRNA transcripts from factors either involved in the adaptive antitumor immune defense (CD3, IFN-γ, IRF-1, IRF-2, SOCS1 and iNOS) or immune tolerance (FoxP3). This study did not reveal an association between urinary neopterin and one of these investigated "on tumor site transcripts". From all the factors reflecting the magnitude of the local adaptive antitumor response, intratumoral IRF-1 expression above the edge of the 25th percentile was found to predict most reliably favorable progression-free (median 34 months vs. 10 months; p < 0.001) and overall (median 52 months vs. 16 months; p < 0.001) survival. In contrast, pre-treatment urinary neopterin excretion above 275 μmol/mol creatinine, which indicates an unspecific activation of the innate immune system, was associated with a very poor overall survival with a median of only 11 months when compared with a median overall survival of 40 months in patients with lower urinary neopterin excretion (p = 0.021). Interestingly, the considerable survival benefit in patients with high IRF-1-expressing cancers was completely abrogated as well for progression-free as for overall survival when urinary neopterin concentrations were found to be concomitantly elevated. These findings demonstrate that in ovarian carcinomas the unspecific "cancer-related inflammation" contributes to a significant subversion of the adaptive antitumor immune defense mounted at the tumor site.

Fig. 1

Univariate survival analyses according to pretherapeutic urinary neopterin levels for progression-free (a) and overall survival (b). Patients exhibiting neopterin levels above a cutoff level of 275 μmol/mol (HIGH) showed poor overall survival, whereas no significant difference in progression-free survival was revealed

Fig. 2

Univariate survival analyses of intratumoral IRF-1 mRNA transcript expression for progression-free (a) and overall survival (b). The cut off between high and low IRF-1 expression was set at the 25th percentile (3.39). High IRF-1 expression at the tumor site was translated into a superior median progression-free survival of 34 versus 10 months and a superior median overall survival of 52 versus 16 months

Fig. 3

Abrogation of the survival advantage (a progression-free survival, b overall survival) of intratumoral IRF-1 mRNA expression >25th percentile in patients with concomitant urinary neopterin levels >275 μmol/mol creatinine

Fig. 4

Survival benefit (a progression-free survival, b overall survival) of intratumoral IRF-1 mRNA expression >25th percentile in the subgroup of patients with normal urinary neopterin excretion