Heterologous Prime-Boost Vaccination with a Peptide-Based Vaccine and Viral Vector Reshapes Dendritic Cell, CD4+ and CD8+ T Cell Phenotypes to Improve the Antitumor Therapeutic Effect

Abstract

Heterologous prime-boost settings with a protein vaccine and the viral vector vesicular stomatitis virus, both expressing tumor-associated antigens (KISIMA-TAA and VSV-GP-TAA), have been previously shown to generate potent antitumor immunity. In the cold TC-1 model (HPV antigen) and the immune-infiltrate MC-38 model (Adpgk, Reps1 and Rpl18 neo-antigens), we further investigated pivotal immune cells that educate CD8+ T cells. Heterologous prime-boost vaccination induced a superior antitumor response characterized by the increase in number and functionality of antigen-specific CD8+ T cells, recruitment of cross-presenting dendritic cells, and polarization of CD4+ T cells towards an antitumor Th1 phenotype within the tumor and tumor-draining lymph nodes, turning the cold TC-1 tumor into a hot, inflamed tumor. In the inflamed MC-38 tumor model, treatment combination markedly prolonged the overall survival of mice. Treatment with multi-epitope vaccines also induced high frequencies of multiple antigen specificities in the periphery and in the tumor. Prime-boost treatment reduced tumor-infiltrating regulatory CD4+ T cells whilst increasing cross-presenting dendritic cells in tumor-draining lymph nodes. In conclusion, heterologous prime-boost vaccination possesses the ability to induce a potent anti-tumor response in both immune-excluded and immune-infiltrated mouse tumor models. Additionally, this study highlights the design of a multi-epitope vaccine for cancer immunotherapy.

Bimodal Effect of NKG2A Blockade on Intratumoral and Systemic CD8 T Cell Response Induced by Cancer Vaccine

“…The combination of protein-based cancer vaccine with oncolytic virus in heterologous prime-boost setting has been previously shown to elicit a robust and durable antigen-specific CD8 T cell response associated with a profound remodeling of the tumor microenvironment, resulting in strong tumor growth inhibition in mouse models [ 7 , 8 ].…”

“…KISIMA—VSV-GP-TAg heterologous prime-boost is a vaccination strategy combining the protein-based cancer vaccine with the oncolytic virus expressing the same tumor antigens. We have previously shown that therapeutic vaccination with KISIMA—VSV-GP-TAg resulted in significantly improved antitumoral efficacy in different mouse tumor models [ 7 , 8 ]. Mechanistically, KISIMA—VSV-GP-TAg vaccination not only elicited a strong peripheral antigen-specific CD8 T cell response but also induced a deep remodeling of the tumor microenvironment (TME) by promoting a significant influx of cytotoxic CD8 T cells and cross-presenting dendritic cells and by decreasing the presence of immune suppressive cells such as M2 tumor associated macrophages (TAM-2) and myeloid derived suppressor cells (MDSCs) [ 7 , 8 ].…”

“…We have previously shown that therapeutic vaccination with KISIMA—VSV-GP-TAg resulted in significantly improved antitumoral efficacy in different mouse tumor models [ 7 , 8 ]. Mechanistically, KISIMA—VSV-GP-TAg vaccination not only elicited a strong peripheral antigen-specific CD8 T cell response but also induced a deep remodeling of the tumor microenvironment (TME) by promoting a significant influx of cytotoxic CD8 T cells and cross-presenting dendritic cells and by decreasing the presence of immune suppressive cells such as M2 tumor associated macrophages (TAM-2) and myeloid derived suppressor cells (MDSCs) [ 7 , 8 ]. Although heterologous prime-boost vaccination was shown to significantly improve tumor growth control, a substantial proportion of intratumoral CD8 T cells became exhausted, thereby limiting efficacy [ 7 ].…”

Neoantigen-specific T cell help outperforms non-specific help in multi-antigen DNA vaccination against cancer

“…This provides an opportunity for vaccine-induced neoantigen-specific CD4 + T cells to provide optimal help and stimulate tumor-specific CD8 + T cells, which can then re-enter the circulation and home to the tumors to kill malignant cells. 53 In addition to their role in the tumor-draining lymph nodes, tumor-specific CD4 + T cells residing in the TME can contribute to tumor resistance, for example, by recruiting 54 , 55 , 56 and providing local help to 57 CD8 + T cells. Which of these mechanisms contributed to the efficacy of the neoHELP vaccine is at present unclear and will be the subject of future studies.…”

Tumor Vaccines: Unleashing the Power of the Immune System to Fight Cancer

“…These engineered viruses have some potential in the delivery of antitumor drugs [233]. Pioneering therapeutic strategies, such as the KISIMA/VSV-GP heterologous prime-boost methodology and the development of adenovirus-based tumor vaccines, have further emphasized the potential of oncolytic virotherapy as a formidable armament in the arsenal of cancer immunotherapy [234].…”