CD8⁺ T cell immunity blocks the metastasis of carcinogen-exposed breast cancer

The link between carcinogen exposure and cancer immunogenicity is unclear. Single exposure to 12-dimethylbenz[a]anthracene (DMBA) at puberty accelerated spontaneous breast carcinogenesis in mouse mammary tumor virus-polyoma middle tumor-antigen transgenic (MMTV-PyMT^tg or PyMT) and MMTV-Her2/neu^tg (Her2) mice. Paradoxically, DMBA-treated PyMT and Her2 animals were protected from metastasis. CD8⁺ T cells significantly infiltrated DMBA-exposed breast cancers. CD8⁺ T cell depletion resulted in severe lung and liver metastasis in DMBA-treated PyMT mice. Besides increasing tumor mutational burden, DMBA exposure up-regulated Chemokine (C-C motif) ligand 21 (CCL21) in cancer cells and heightened antigen presentation. CCL21 injection suppressed breast cancer growth, and CCL21 receptor deletion attenuated T cell immunity against cancer metastasis in DMBA-treated PyMT animals. CCL21 expression correlated with increased mutational burden and cytolytic activity across human cancers. Higher CCL21 levels correlated with increased CD8⁺ T cell infiltrates in human breast cancer and predicted lower breast cancer distant recurrence rate. Collectively, carcinogen exposure induces immune-activating factors within cancer cells that promote CD8⁺ T cell immunity against metastasis.