Using murine oncogene models of spontaneous breast cancer, Li and Li et al. showed that carcinogen (7,12-dimethylbenz[a]anthracene (DMBA)) exposure reduced lung metastasis, but not primary tumor growth, in CD8+ T cell-dependent manner. DMBA exposure increased CD8+ T-to-Treg ratio in tumors and tumor-draining lymph nodes, and increased TMB, CCL21 expression, and MHC-II+ APCs in breast tumors. CCL21 injection reduced tumor growth, and blockade of the CCL21-CCR7 axis diminished T cell-mediated anti-metastasis immunity. In breast cancer patients, CCL21 expression correlated with increased CD8+ T cell infiltration and reduced risk of distant recurrence.
Contributed by Shishir Pant
ABSTRACT: 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.