Clec9A is a key cDC1-restricted receptor that can be a promising target for cancer immunotherapy due to its great efficacy in cross-presentation and subsequent priming of CD8+ T cells. We have generated anti-Clec9A monoclonal antibody (mAb), genetically fused with an MHC-I model antigen, ovalbumin (OVA). However, a homologous prime-boost vaccination with anti-Clec9A mAb induced cross-reactivity, leading to failure in boosting the immune response. For this reason, we employed an additional cDC1-targeting cancer vaccine, which is alpha-galactosylceramide (αGalCer)-OVA conjugate vaccine.
Liver metastases occur within about 30% of the patients with colorectal or breast cancer, resulting in a poor prognosis and the rate of recurrence is high. However, there is no effective treatment available, rather than surgery. Many lines of evidence highlight the role of TRM cells in anti-tumour immunity because they can provide superior, site-specific protection. Thus, we report a heterologous vaccination with Clec9A-prime and αGalCer-boost effectively enhanced both systemic and local memory response, including expansion of antigen-specific hepatic TRM cells. Interestingly, there was a similar level of effector memory T cell response induced by prime-alone and prime-boost group, which was also accompanied with equivalent anti-tumour activity shown in a murine model of liver melanoma metastases, indicating there might be different underlying mechanisms involved in the antigen processing pathway. Although we did not demonstrate the critical involvement of TRM-based immunity in fighting metastatic melanoma, our findings contribute to the development of a greater vaccination strategy to optimise the efficacy of cDC-targeted vaccines.