The aberrant activation of the transcription factor Stat3 has been described for many cancers including colon cancer. Tumour cell intrinsic Stat3 signalling drives hallmarks of cancer, such as resistance to cell death and sustained proliferation. The effect of aberrant Stat3 activation among tumour infiltrating immune cells however, is yet to be fully elucidated. We postulate that hyper-Stat3 activation in the tumour microenvironment develops an immunosuppressive, pro-tumorigenic environment. We then hypothesise that Stat3 suppression in the non-tumoural cell compartment will inhibit colorectal tumour growth, by dampening this pro-tumour phenotype. Furthermore, we investigated, whether non-tumoural Stat3 suppression synergistically enhances the effects of immunotherapy.
We generated the shStat3 mouse that utilizes short hairpin (sh) RNAi technology allowing for conditional and reversible Stat3 reduction. To study the effects of Stat3 suppression in the non-tumoural compartment, the shStat3 mice were subcutaneously engrafted with MC38 murine colon cancer cells. Anti-tumour effects of Stat3 suppression were assessed either alone or in combination with immune checkpoint blockade, specifically anti-PD1 antibody treatment.
We found, that Stat3 suppression in the non-tumoural compartment alone suppresses MC38 colon tumour growth. Immunophenotyping of excised tumours revealed an increase of monocytic Ly6C+Ly6G- myeloid cells. While checkpoint blockade alone reduced tumour growth similarly to Stat3 suppression, there was no additive or synergistic effect of Stat3 reduction in combination with anti-PD1 treatment.
Our data suggest that combination of STAT3 inhibitors with anti-PD1 blockade do not offer greater therapeutic outcome when treating anti-PD1 sensitive microsatellite instable (MSI) classified MC38 colon cancer cells, which then advises against the use of this combination for colorectal cancer patients with this classification. However, we identified Stat3 signalling within the tumour microenvironment as part of the anti-tumoural activity of Stat3 targeting strategies, with monocytic myeloid cells being a candidate cell type driving these responses.