To understand the role of innate immunity, particularly dendritic cells, in neoadjuvant checkpoint immunotherapy, Liu et al. evaluated the impact of knockout of batf3, a transcription factor that identifies a key subset of cross-presenting DCs, and blockade of type I IFN signaling. Batf3+ DCs and IFN signaling were required for efficacy of neoadjuvant immunotherapy in a mouse breast cancer model, impacting increases in antigen-specific TILs. Neoadjuvant immunotherapy increased the number and activation of CD103+ DCs in the draining, but not non-draining, lymph node. Human correlates with efficacy and batf3-associated genes were observed in a small trial.
New clinical trials are now evaluating the efficacy of neoadjuvant immunotherapy in the context of primary tumor surgery. Using the orthotopic 4T1.2 mouse model of spontaneously metastatic mammary cancer, we have shown that neoadjuvant immunotherapy and surgery was superior in the generation of tumor-specific CD8+ T cells and eradication of lethal metastases compared to surgery followed by adjuvant immunotherapy. However, the importance of host Batf3 and type I interferon (IFN) for long-term survival of mice following neoadjuvant immunotherapy is unknown. Here we demonstrated that loss of Batf3+ DCs or type I IFN receptor blockade in 4T1.2 tumor-bearing mice treated with neoadjuvant anti-PD-1+anti-CD137 immunotherapy reduced long-term survival with a corresponding reduction in tumor-specific CD8+ T cells producing effector cytokines in the primary tumor and in the periphery. Interestingly, we found all high-risk stage III melanoma patients relapsing after adjuvant or neoadjuvant ipilimumab+nivolumab within the OpACIN trial (NCT02437279) displayed low expression of Batf3+ DC-associated genes in pre-treatment tumor biopsies. Further focus should now be placed on validating the requirement of an intratumoral Baft3+ DC gene signature for response to neoadjuvant immunotherapy.
Author Info: (1) Cancer Immunoregulation and Immunotherapy Laboratory, QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia; (2) Division of Molecular Oncology & immunology
Author Info: (1) Cancer Immunoregulation and Immunotherapy Laboratory, QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia; (2) Division of Molecular Oncology & immunology, Nerthelands Cancer Institute - Antoni van Leeuwenhoek Hospital, Amsterdam, the Netherlands; (3) Immunology in Cancer and Infection Laboratory, QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia; (4) School of Medicine, University of Queensland, Herston, Queensland, Australia
