Tumor microenvironment modulation therapy in breast-cancer-subtypes and single-cell genomics-based patient stratification for improved low-dose immunotherapy: Preclinical and Clinical study

This study is a non-randomized open-label, single-centre trial.

 Immuno-suppressive-tumor-microenvironment (TME) is responsible for poor clinical response to cancer immunotherapy. Our study found that depleting MDSCs and repolarizing M2-macrophages-to-M1, enhance infiltration of lymphocytes in the TME, leading to excellent tumor control in animal models. Further, our Breast cancer TME profiling in humans revealed the association between MDSCs and PD1hi-exhausted T-cells. Overcoming TME immunosuppression is critical for improved clinical outcomes, especially for immunotherapy of difficult-to-treat breast cancers like Luminal B-Her2-ve and Triple-negative breast cancer (TNBC). Though the significance of PD-L1/CTLA4 expression in cancer is known, the critical roles of MDSCs, N2 neutrophils, regulatory-B, -DCs, and -NK cells in different BC subtypes are unknown. The impact of metronomic anti-TME therapy for improving low-dose-ICB response in TNBC is also unknown. This study plans to examine whether overcoming immune-suppressive TME using metronomic-chemotherapy and TME-based patient stratification can improve the therapeutic outcome in response to low-dose-ICB in breast cancer subtypes with poor prognosis. This approach will be safer, affordable, and more efficacious. The primary outcomes expected are, 1. A novel anti-TME approach to sensitize Luminal B-Her2-ve and TNBC patients to low-dose, affordable, and safer ICB; 2. Utility of anti-TME therapy for improving prognostication of Luminal-B/Her2-ve Breast cancer subtype. 3. High-resolution single-cell data on metronomic anti-TME therapy in breast cancer.