Chemotherapy enhances cancer vaccine efficacy and expands stem-like TCF1+CD8+ T cells
(1) Noblecourt L (2) Wicki A (3) Jainarayanan A (4) Pereira-Almeida V (5) McAuliffe J (6) Steffke E (7) Panetti S (8) Fuchs H (9) Ramirez-Valdez RA (10) Chandrasekar V (11) Cai Y (12) Boekestijn S (13) Hill AVS (14) Gerard A (15) Welters MJP (16) Van der Burg SH (17) Pedroza-Pacheco I (18) Van den Eynde BJ (19) Leung CSK
Noblecourt and Wicki et al. showed that carboplatin and paclitaxel (CarboTaxol) with viral vector vaccines expanded antigen-specific TCF1+CD8+ T cells during priming, slowed tumor growth, and improved survival in mouse models. Acting as an adjuvant, CarboTaxol induced early tumor- and vaccine-independent expansion of stem-like TCF1+CD8+ T cells that depended on TCF1/β-catenin activity. Adding PD-1 blockade to chemotherapy and cancer vaccines further improved tumor control and long-term survival. Expansion of TCF7+CD8+ T cells was also seen in ovarian and cervical cancer patients treated with CarboTaxol.
Contributed by Katherine Turner
(1) Noblecourt L (2) Wicki A (3) Jainarayanan A (4) Pereira-Almeida V (5) McAuliffe J (6) Steffke E (7) Panetti S (8) Fuchs H (9) Ramirez-Valdez RA (10) Chandrasekar V (11) Cai Y (12) Boekestijn S (13) Hill AVS (14) Gerard A (15) Welters MJP (16) Van der Burg SH (17) Pedroza-Pacheco I (18) Van den Eynde BJ (19) Leung CSK
Noblecourt and Wicki et al. showed that carboplatin and paclitaxel (CarboTaxol) with viral vector vaccines expanded antigen-specific TCF1+CD8+ T cells during priming, slowed tumor growth, and improved survival in mouse models. Acting as an adjuvant, CarboTaxol induced early tumor- and vaccine-independent expansion of stem-like TCF1+CD8+ T cells that depended on TCF1/β-catenin activity. Adding PD-1 blockade to chemotherapy and cancer vaccines further improved tumor control and long-term survival. Expansion of TCF7+CD8+ T cells was also seen in ovarian and cervical cancer patients treated with CarboTaxol.
Contributed by Katherine Turner
ABSTRACT: Therapeutic cancer vaccines are increasingly tested in clinical settings alongside standard-of-care treatments that often include chemotherapy, yet whether chemotherapy synergizes with cancer vaccines remains unclear. Here, we tested heterologous prime-boost viral vector vaccines in combination with various chemotherapy regimens. Both carboplatin plus paclitaxel (CarboTaxol) and cyclophosphamide improve vaccine efficacy and enhance antigen-specific CD8(+) T cell responses. These chemotherapies act as immunological adjuvants independently of tumor presence. Mechanistically, CarboTaxol induces an early, antigen-independent expansion of stem-like T cell factor 1 (TCF1)(+)CD8(+) T cells, an effect also observed in patients with different cancer types. Genetic or pharmacological disruption of TCF1 impairs the immunological adjuvant effect of CarboTaxol. Adding programmed cell death 1 (PD-1) blockade to viral vector vaccines and CarboTaxol further improves tumor control and survival. Together, these findings identify a TCF1-dependent mechanism underlying the immune adjuvant effect of chemotherapy and provide a rationale for clinical evaluation of this triple combination therapy.
Author Info:
(1) Ludwig Institute for Cancer Research, Nuffield Department of Medicine, University of Oxford, Oxford, UK. (2) Ludwig Institute for Cancer Research, Nuffield Department of Medici
ne, University of Oxford, Oxford, UK. (3) Kennedy Institute of Rheumatology, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford, UK. (4) Ludwig Institute for Cancer Research, Nuffield Department of Medicine, University of Oxford, Oxford, UK. (5) Ludwig Institute for Cancer Research, Nuffield Department of Medicine, University of Oxford, Oxford, UK. (6) Ludwig Institute for Cancer Research, Nuffield Department of Medicine, University of Oxford, Oxford, UK. (7) Ludwig Institute for Cancer Research, Nuffield Department of Medicine, University of Oxford, Oxford, UK. (8) Ludwig Institute for Cancer Research, Nuffield Department of Medicine, University of Oxford, Oxford, UK. (9) Ludwig Institute for Cancer Research, Nuffield Department of Medicine, University of Oxford, Oxford, UK. (10) Ludwig Institute for Cancer Research, Nuffield Department of Medicine, University of Oxford, Oxford, UK. (11) Centre for Immuno-Oncology, Nuffield Department of Medicine, University of Oxford, Oxford, UK. (12) Department of Medical Oncology, Oncode Institute, Leiden University Medical Center, Albinusdreef, 2, 2333 ZA Leiden, the Netherlands. (13) Jenner Institute, Nuffield Department of Medicine, University of Oxford, Oxford, UK. (14) Kennedy Institute of Rheumatology, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford, UK. (15) Department of Medical Oncology, Oncode Institute, Leiden University Medical Center, Albinusdreef, 2, 2333 ZA Leiden, the Netherlands. (16) Department of Medical Oncology, Oncode Institute, Leiden University Medical Center, Albinusdreef, 2, 2333 ZA Leiden, the Netherlands. (17) Centre for Immuno-Oncology, Nuffield Department of Medicine, University of Oxford, Oxford, UK. (18) Ludwig Institute for Cancer Research, Nuffield Department of Medicine, University of Oxford, Oxford, UK; Ludwig Institute for Cancer Research, de Duve Institute, UCLouvain, Brussels, Belgium; WEL Research Institute, Brussels, Belgium. Electronic address: benoit.vandeneynde@ludwig.ox.ac.uk. (19) Ludwig Institute for Cancer Research, Nuffield Department of Medicine, University of Oxford, Oxford, UK; Centre for Immuno-Oncology, Nuffield Department of Medicine, University of Oxford, Oxford, UK. Electronic address: carol.leung@immonc.ox.ac.uk.
