Perivascular macrophages restrict CXCR4-dependent accumulation of stem-like CD8+ T cells in tumors and limit chemotherapy efficacy

The perivascular (Pv) niche coordinates immune-stromal interactions that facilitate cancer progression. Pharmacological inhibition or genetic inactivation of the enzyme heme oxygenase-1 (HO-1) in LYVE-1 + Pv tumor-associated macrophages (PvTAMs) synergizes with cytotoxic chemotherapy (CCT) to achieve immunological tumor control in murine breast cancer models. We investigated the tumor microenvironment (TME) during the transition to immunological control and identified an increase in stem-like TCF1 + PD-1 + CD8 + T cells and enrichment of tumor-selective effector T cells. Stem-like CD8 + T cells were clonally diverse and rapidly acquired a TCF1 − differentiated phenotype in the TME. Their tumor accumulation depended on CXCR4 and was associated with a treatment-induced expansion of proliferating CXCL12 + CD34 + Pv cancer-associated fibroblasts (CAFs). In human breast cancer, greater abundance of the stem-like CD8 + T cell program was associated with improved outcomes following CCT. These findings identify PvTAM HO-1 activity as a regulator of a stromal-stem-like T cell axis that limits chemotherapy efficacy and anti-tumor immunity.