Loss of tumor-inherent type I interferon (IFN) signaling has been linked to decreased anti-tumor immunity and accelerated metastatic progression. Suppressed tumor cell IFN production and response has multiple effects on cancer-specific immune responses, including dampened MHC-I antigen presentation that renders tumor cells ‘invisible’ to adaptive immune cells. Our previous studies in murine models of triple negative breast cancer (TNBC) demonstrate that IFN-inducers can suppress metastatic progression. To avoid toxicities associated with systemic IFN administration, the use of alternate intratumoral IFN inducers is an active area of investigation.
Using two pre-clinical models of TNBC - the type I IFN-intact, weakly metastatic E0771 model and the IFN-supressed, highly metastatic 4T1.2 model, we assessed the impact of intratumoral injection of the TLR7/8 agonist 3M-052 in a neoadjuvant setting on TME immunogenicity, metastatic progression and overall survival.
We demonstrate that intratumoral 3M-052 completely remodels the immune TME in the absence of non-specific systemic immune activation. Single administration of 3M-052 was sufficient to decrease primary tumor size and suppress metastatic spread via enhanced tumor-specific CD8+ T cell expansion and decreased Treg and M2 macrophages, an impact far superior to anti-PD1 therapy. Tumor-specific CD8+ T cell responses were enhanced in combination with neoadjuvant chemotherapy. 3M-052 action was IFN-dependent, via DC activation and production of IFN and other pro-inflammatory cytokines to initiate a T cell-inflamed tissue microenvironment (TME) and promote tumor antigen presentation. Our results indicate that a single intratumoral treatment can induce TME immunoreactivity that is capable of inducing long-term protection from metastasis through formation of immunological memory and suggests that trialling IFN inducers in TNBC patients is warranted.