In this study, we have confirmed the expression of MMP11 in breast and prostate cancer (Figure
1) and for the first time we have found its expression in bloodstream and spontaneous autoantibodies in breast and prostate cancer patients (Figures
2 and
3). The prognostic significance of MMP11 expression for breast cancer was recently confirmed by Cheng
et al.[
13]. Overexpression of MMP-11 correlates with patients having poorly differentiated tumors, lymph node metastasis and lacking progesterone receptor. Temporally increased MMP-11 expression can be considered as an early event, occurring prior to lymph node metastasis during breast cancer progression. Similarly, MMP11 expression in prostate cancer patients was significantly correlated with poor differentiation in Gleason grading, pathologic tumor stage4 (pT4), and positive-bone metastasis (p < 0.05), but not age and prostatic-specific antigen (PSA) level. Patients with high levels of MMP-11 expression demonstrated significantly shorter survival (p < 0.001) when compared to those with low levels[
14]. Therefore, high levels of MMP11 may potentially be used for prediction of a poor prognosis.
Our data show that MMP11 is indeed overexpressed in a subset of breast and prostate cancer patients. In our breast cancer specimens we were able to detect the expression either by the cancerous cells (Figure
1A) or by the peritumoral fibroblasts (Figure
1B). We also found a strong signal in 3/5 prostate cancer samples (Figure
1C). The presence of autoantibodies is in line with this finding. We are currently developing an assay to specifically detect and quantify MMP11 catalytic activity on a synthetic substrate peptide. Such assay will be instrumental to assess whether spontaneous and induced antibodies against MMP11 could have a biological role at inhibiting its enzymatic activity. Moreover, it will be of interest to find association among the circulating protein, the antibody titer and patients survival. We are currently following up these patients, accumulating new data and analyzing the IgG subtype to find potential associations. A limitation of our study is the restricted data set and the lack of match between MMP11 tumor expression and plasma samples within the same patients population. For this reason, our finding needs to be followed by a confirmatory study with a larger cohort of patients. Moreover, the observation that one healthy donor (C015, Figure
2) showed a high level of circulating MMP11 suggest that the protein may be involved in other biologic processes and indicate that larger patients cohorts and relative controls should be analyzed. In addition, we are generating preclinical data in mouse models that suggest that cell mediated immune response may play an important role as effective arm of the immune response as a consequence of an anti-MMP11 vaccination. A novel T-cell epitope derived from human MMP11 (hMMP
237) was identified in our lab by vaccination of HLA-A2.1 (HHD) transgenic mice and was shown to be immunogenic by
in vitro priming with human PBMCs. Moreover, activated CTLs secrete granzyme B, a key mediator of target cell death via the granule-mediated pathway[
10]. Thus, the immune response against hMMP
237 represents a potential biomarker for induced and spontaneous immune response. We are currently analyzing by tetramer staining and
in vitro priming the T cell responses in PBMCs from patients affected by different tumor types, including breast and prostate cancer. It will be of interest to correlate IHC, circulating protein, antibodies and T cell responses with clinical behavior and survival outcome.
In conclusion, our study, albeit preliminary, further suggest that MMP11 may act as a bona fide TAA and be a suitable target for cancer immunotherapy.