Background: Aberrant activation of the transcription factor Stat3 promotes tumorigenesis through increased tumour cell proliferation and survival, but also through pro-tumorigenic manipulation of the tumour-infiltrating immune cells. This project aims to determine the tumourigenic role of Stat3 not only among the tumour cells but also of the non-tumoural compartment.
Methods: To study the effect(s) of specific Stat3 inhibition, we exploited the inducible CAGsrtTA3;STAT3.1348 (shStat3;rtTA)1 and RosaCreERT2;Stat3fl/fl mice that allows for the ubiquitous reduction or deletion of Stat3 respectively. The shRNA;rtTA mice were crossed with the gp130F/F generating the shRNA;rtTA;gp130F/F compound mice, previously described to spontaneously develop gastric polyps1,2, to investigate the effect(s) of ubiquitous Stat3 reduction on gastric tumour growth. Furthermore, to investigate the role of Stat3 suppression exclusively among the non-tumoural compartment, the shStat3;rtTA and RosaCreERT2;Stat3fl/fl mice were engrafted with MC38 (murine colon cancer) cells, where Stat3 reduction only occurs among the non-tumoural compartment. Additionally, Stat3 suppression was also combined with the immunotherapy anti-PD-1 treatment.
Results: Stat3 reduction in the shRNA;rtTA;gp130F/F mice resulted in significant gastric tumour reduction. Our shStat;rtTA MC38-colon cancer allograft experiments showed that Stat3 suppression alone resulted in a significant reduction in tumour burden, to a similar extent as single treatment anti-PD-1. Consistently RosaCreERT2;Stat3fl/fl allografts also showed that Stat3 suppression among the non-tumoural compartment alone significantly reduces tumour burden, however the anti-PD-1 treatment alone did not exhibit anti-tumoural effects in this model. Interestingly, in both the shStat3;rtTA and RosaCreERT2;Stat3fl/fl allograft experiments there was no additive/synergistic effect observed in combination with immunotherapy. Immunoprofiling of these MC38 tumours revealed a possible role of anti-tumourigenic Ly6C+Ly6G- monocytic cells in mediating the anti-tumour effect seen among the Stat3 reduced mice.
Conclusion: Our findings provide compelling evidence that Stat3 suppression in the non-tumoural compartment results in a significant tumour reduction. Further investigations determining the exact cellular population(s) contributing to the pro-tumorgenic effect of Stat3 activation will expose novel therapy targets and might help to predict anti-tumour responses to Stat3 inhibition.