mRNA-based dendritic cell immunization improves survival inrettransgenic mouse melanoma model

Abstract

Malignant melanoma is characterized by a rapid progression, metastasis to distant organs and resistance to chemo and radiotherapy. Although melanoma is capable of eliciting an immune response, the disease progresses and the overall results of immunotherapeutic clinical studies are not satisfactory. Recently, we have developed a novel genetic platform for improving an induction of peptide-specific CD8 C T cells by dendritic cell (DC) based on membrane-anchored b2-microglobulin (b2m) linked to a selected antigenic peptide at the N-terminus and to the cytosolic domain of TLR4 at the C-terminus. In vitro transcribed mRNA transfection of antigen-presenting cells (APCs) resulted in an efficient coupling of peptide presentation and cell activation. In this research, we utilize the chimeric platform to induce an immune response in ret transgenic mice that spontaneously develop malignant skin melanoma and to examine its effect on the overall survival of tumor-bearing mice. Following immunization with chimeric construct system, we observe a significantly prolonged survival of tumor-bearing mice as compared to the control group. Moreover, we see elevations in the frequency of CD62L hi CD44 hi central and CD62L lo CD44 hi effector memory CD8C T-cell subsets. Importantly, we do not observe any changes in frequencies of regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs) in the vaccinated groups. Our data suggest that this novel vaccination approach could be efficiently applied for the immunotherapy of malignant melanoma.

A universal anti‐cancer vaccine: Chimeric invariant chain potentiates the inhibition of melanoma progression and the improvement of survival

“…40,41 We have previously shown that the universal MHC-I chimeric mRNA construct vaccine, which couples antigen presentation and activation of DCs via caTLR4, inhibited tumor growth and improved survival of melanoma bearing mice. [15][16][17][18] The system is based on the covalent linkage of an antigenic peptide to the non-polymorphic β2m chain of the MHC-I molecule. In our study, we aimed at broadening the clinical potential of the system by designing two additional MAA MHC-I constructs.…”

“…This is consistent with our previously published data that a combination of MHC-I restricted gp100 and TRP2 chimeric constructs is beneficial over immunization with a single construct. 16 Such results might indicate that multiple antigenic presentations are required to exert an efficient anti-tumor immune response.…”

“…13,14 We have previously generated chimeric polypeptides with MAAs specific to gp100 [25][26][27][28][29][30][31][32][33] and TRP2 180-188 and tested their antitumor activity both in a transplantable B16 and in a spontaneous ret melanoma model. 15,16 To broaden the clinical potential of the constructs and to allow combinations with MHC-I MAAs, we used the SYFPEITHI prediction software. Among several MHC-I tested peptides (Supporting Information Fig.…”

“…We have previously demonstrated that the combined immunization with both the gp100 [25][26][27][28][29][30][31][32][33] and TRP2 180-188 constructs inhibited tumor growth and prolonged mouse survival. 15,16 Here, on day 0, mice were inoculated with Ret melanoma cells and monitored daily (Fig. 3a).…”

“…14 This modality was highly efficient in inhibiting tumor growth and improving survival, both in transplantable and spontaneous melanoma mouse models. 15,16 In our study, we aimed to broaden the clinical potential of these constructs by developing a novel MHC-II universal vaccine platform, which facilitates DCs to activate CD4 + T cells and enhances the anti-tumor response. We have generated a chimeric invariant chain (Ii), where the semi-peptide CLIP is replaced with an MHC-II MAAs.…”