Hypoxia induces HIF1α-dependent epigenetic vulnerability in triple negative breast cancer to confer immune effector dysfunction and resistance to anti-PD-1 immunotherapy.

The hypoxic tumor microenvironment has been implicated in immune escape, but the underlying mechanism remains elusive. Using an in vitro culture system modeling human T cell dysfunction and exhaustion in triple-negative breast cancer (TNBC), we find that hypoxia suppresses immune effector gene expression, including in T and NK cells, resulting in immune effector cell dysfunction and resistance to immunotherapy. We demonstrate that hypoxia-induced factor 1α (HIF1α) interaction with HDAC1 and concurrent PRC2 dependency causes chromatin remolding resulting in epigenetic suppression of effector genes and subsequent immune dysfunction. Targeting HIF1α and the associated epigenetic machinery can reverse the immune effector dysfunction and overcome resistance to PD-1 blockade, as demonstrated both in vitro and in vivo using syngeneic and humanized mice models. These findings identify a HIF1α-mediated epigenetic mechanism in immune dysfunction and provide a potential strategy to overcome immune resistance in TNBC.

Correlation between the protein expression levels of A-kinase anchor protein95, p-retinoblastoma (Ser780), cyclin D2/3, and cyclin E2 in esophageal cancer tissues.

AIM: This study aimed to investigate the correlation between the expression of A-kinase anchor protein95 (AKAP95), p-retinoblastoma (phosphorylated Rb, p-Rb), cyclin D2, cyclin D3 and cyclin E2 in esophageal cancer tissues and clinicopathological indexes. METHOD: The protein expression levels of AKAP95, p-Rb, cyclin D2/3 and cyclin E2 in 40 esophageal cancer tissues were detected using immunohistochemistry, and the correlation between them was analyzed. RESULT: The percentage of p-Rb (Ser780)-, cyclin D2-, cyclin D3- and cyclin E2-positive samples was 62.50%, 70.00%, 67.50% and 60.00%, respectively. Also, the positive expression did not correlate with the histological type, histological differentiation or lymph node metastasis. The expression of AKAP95 and p-Rb (Ser780), p-Rb (Ser780) and cyclin D2 and p-Rb (Ser780) and cyclin D3 in esophageal cancer tissues was found to be correlated (P < 0.05). CONCLUSIONS: The expression of AKAP95 and p-Rb (Ser780), p-Rb(Ser780) and cyclin D2, and p-Rb (Ser780) and cyclin D3 in esophageal cancer tissue was correlated, suggesting that these proteins might play a synergistic role in cell-cycle progression. Cyclin D2/D3 and p-Rb (Ser780) were correlated whereas cyclin E2 and p-Rb (Ser780) were not, suggesting that p-Rb (Ser780) might be highly expressed and the Ser780 site of Rb protein might be phosphorylated in the early stage of the G1 phase. Ser780 was the site in the primary phosphorylation stage of several phosphorylation sites during stepwise phosphorylation (from primary to high phosphorylation).