Chemotherapy synergizes with cancer vaccines and expands stem-like TCF1+CD8+ T cells

Therapeutic cancer vaccines, whether based on neoantigens or shared antigens, will likely be given in the clinic together with the standard of care, which often comprises immune checkpoint blockade therapy and chemotherapy. It remains unclear, however, whether vaccines effectively synergize with chemotherapy. Here, we tested the combination of a heterologous prime-boost viral vector vaccine with chemotherapy (CarboTaxol) and anti-PD- 1. We show that this triple combination improves tumor control and survival in different murine tumor models. CarboTaxol, and also cyclophosphamide, acted as an immune adjuvant for the vaccines, enhancing tumor-specific CD8+ T-cell responses, irrespective of the presence of a tumor. These chemotherapies expanded stem-like T cell factor 1 (TCF1)+CD8+ T cells. Inhibition of the transcriptional activity of TCF1/β-catenin with a small molecule inhibitor abolished the immune adjuvant effect of CarboTaxol. This study sheds light on the new immunomodulatory roles of chemotherapies and holds promises for clinical testing of this combination strategy. Highlights ### Competing Interest Statement A.V.S.H., B.J.V.D.E., and C.S.L. are inventors on a patent that covers viral vectors and methods for the prevention and treatment of cancer. A.V.S.H. is a co-founder of and shareholder in Barinthus Biotherapeutics Ltd which has supported the MAGE cancer vaccine program and has licensed rights to the ChAdOx1-MVA platform in cancer. B.J.V.D.E. is a scientific advisor in Barinthus Biotherapeutics Ltd. All other authors declare no conflict of interest.