Maximizing the Anti-Tumor Potential of Immune Checkpoint Blockade through Modulation of Myeloid-Specific CXCL16 and STAT1 Signaling

Sensitivity to immune checkpoint blockades (ICB) depends on the overall balance of immunogenic and immunosuppressive signals in the tumor immune microenviron- ment (TIME). Chemotherapy as an immunostimulatory strategy showed potential in improving ICB’s clinical efficacy. Yet, evolution of highly plastic tumor-associated myeloid cells hinders ICB’s potential to reach its full therapeutic potential. In this study, we leveraged single-cell transcriptomic and trajectory analyses to delineate TIME dynamics after chemotherapy priming. We found that metronomic chemother- apy (MCT) treatment led to an accelerated T cell exhaustion through CXCL16- mediated recruitment of peripheral immature myeloid cells and expansion of STAT1- driven PD-L1 expressing myeloid cells. Inhibiting STAT1 signaling in MCT-primed breast cancer relieved T cell exhaustion and significantly enhanced the efficacy of anti-PD-1 ICB treatment. Our study leveraged single-cell analyses to dissect the dynamics of breast cancer TIME and provides a pre-clinical rationale to translate the anti-STAT1 plus anti-PD-1 combinatorial immunotherapy regimen to maximize ICB’s efficacy.