Interferon Signaling is Diminished with Age and is Associated with Immune Checkpoint Blockade Efficacy in Triple-Negative Breast Cancer

Immune checkpoint blockade (ICB) therapy, which targets T-cell inhibitory receptors, has revolutionized cancer treatment. Among the breast cancer subtypes, evaluation of ICB has been of greatest interest in triple negative breast cancer (TNBC) due to its immunogenicity, as evidenced by the presence of tumor infiltrating lymphocytes and elevated PD-L1 expression relative to other subtypes. TNBC incidence is equally distributed across the age spectrum, affecting 10-15% of women in all age groups. Here we report that increased immune dysfunction with age limits ICB efficacy in aged TNBC-bearing mice. The tumor microenvironment in both aged mice and TNBC patients shows decreased interferon (IFN) signaling and antigen presentation, suggesting failed innate immune activation with age. Triggering innate immune priming with a STING agonist restored response to ICB in aged mice. Our data implicate age-related immune dysfunction as a mechanism of ICB resistance in mice and suggest potential prognostic utility of assessing IFN-related genes in TNBC patients receiving ICB therapy.