The Immunomodulatory Role of Gemcitabine in Triple Negative Breast Cancer

Triple negative breast cancer (TNBC), defined for its lack of expression/amplification of three major receptors, makes up ~15% of all BC cases but a majority of all BC deaths. TNBC has been found to be the most immune-rich among BC subtypes, and progress has been made in the development of immunotherapies; however, not all patients are eligible, and response can be limited. Therefore, there is a significant clinical need to enhance the response to these treatments. Given chemotherapy is the core component of TNBC treatment, and is given in combination with immunotherapy, its potential immunomodulatory impact warrants exploration. Gemcitabine, currently used for the treatment of metastatic TNBC, has been reported to have potential immunomodulatory properties that create a more immune-favourable TME for combination with immunotherapies and/or improved outcome. We therefore investigated the use of gemcitabine as an immunomodulator in a primary 4T1 TNBC mouse model. Gemcitabine was able to reduce pro-tumour immune cells including macrophages and MDSCs while increasing T-cell abundance, therefore resulting in a less immunosuppressive TME. We demonstrated that this immune response was both temporal and dose-dependent, which has impact for planning and scheduling combination treatments. In conclusion, we have demonstrated that gemcitabine modulates the TME in ways that could not only enhance the direct anti-tumour effects of gemcitabine itself but also potentially enhance responsiveness to immunotherapy. This work has laid the foundation for further studies investigating combination therapy for the treatment of TNBC.