Tractable mouse TNBC models capture the heterogeneous tumor immune microenvironment and adaptation to PD-L1 blockade

Triple-negative breast cancer (TNBC) patients exhibit variable responses to programmed death (PD)-ligand (L)1 blockade, largely determined by the ‘hot’ versus ‘cold’ state of the tumor immune microenvironment (TIME). We here characterized 9 mouse TNBC models, relying on intraductal mammary gland inoculation of established mouse TNBC cell lines, with a heterogeneous TIME to study anti-PD-L1 resistance mechanisms. Complementary in vitro and in vivo screening classified the 4T1-hot-based model, a highly inflamed control through its immunogenic luciferase tag expression compared to the untagged 4T1-cold-based model, as displaying the ‘hottest’ TIME. However, both 4T1-based counterparts did not respond to anti-PD-L1, which was attributed to their immunosuppressive myeloid cell content as well as upregulation of cancer-associated fibroblasts in the 4T1-hot and high PD-L1-expressing CXCL10+ tumor-associated macrophages in 4T1-cold primary tumors. These anti-PD-L1 adaptation mechanisms across TIME states as captured by mouse TNBC models highlight specific cellular targets for future studies.