Triple negative breast cancer (TNBC) is a highly aggressive form of breast cancer resulting in poor prognoses for patients with metastatic disease, exacerbated by a lack of targeted therapy options. Among the immunotherapies showing convincing benefit in certain clinical settings, cancer vaccines are emerging as a highly promising treatment option. However, vaccines have largely fallen short for TNBC, with the optimisation of antigen delivery systems and rational selection of combination approaches to overcome local and systemic immunosuppression yet to be defined.
A novel vaccine platform exploits tailorable nano-emulsions functionalised to selectively deliver tumour antigens to Clec9A+ cross-presenting dendritic cells in vivo, resulting in the expansion of tumour-specific CD4+ and CD8+T cells without the need of adjuvants. (Zeng et al., 2018). In immune-evasive tumour models, including B16F10 melanoma and A20 lymphoma, vaccination effectively reversed the downregulation of MHC-I and MHC-II that characterizes these malignancies through an IFN-α-driven mechanism. This restoration of antigen presentation led to the induction of a robust antitumour immune response and significantly prolonged metastasis-free survival.
In contrast, the chronically immunosuppressive microenvironment of TNBCs severely impairs vaccine-immunity, limiting the ability of tumour-specific T cells to achieve durable control of tumour progression. To enhance the efficacy of neoantigen-based Clec9A-targeting vaccination in the aggressive 4T1.2 TNBC model, we identified STAT3 as an actionable therapeutic target, given its hyperactivation within the TIME and strong correlation with poor patient prognosis. We therefore leveraged the JAK1/2 inhibitor Ruxolitinib to suppress STAT3 hyperactivation and alleviate chronic immunosuppression.
Combined treatment with Clec9A-targeting vaccination and Ruxolitinib achieved significant early and sustained control of primary tumour growth. In neoadjuvant settings, more than 50% of treated mice remained metastasis-free after surgical resection of the primary tumour, with this survival benefit associated with a significant reduction of lung metastatic burden.
Mechanistically, decreased lung metastasis correlated with enhanced recruitment of CD3+T cells and mature, cytotoxic NK cells, which displayed increased activation and reduced exhaustion phenotypes. Ongoing studies highlight a critical contribution of unconventional gdT cells, as their depletion significantly diminished the combination therapy induced control of primary tumour growth. The treatment also profoundly remodelled myeloid-derived suppressor cells populations within the TIME. Moreover, preliminary findings suggests that therapeutic benefit may be further enhanced by incorporating adjuvant immune checkpoint blockade.
From a clinical perspective, these results support a precision immunotherapy strategy in which vaccine-based treatments are tailored to the immune context of each tumour depending on the dominant mechanism of immune-escape.