Beyranvand Nejad et al. showed that suboptimal HPV16 E7 peptide vaccination of E7+ tumor-bearing mice induced specific T cell responses that mediated tumor regression, but allowed regrowth that could not be prevented by using anti-PD-1. Relapsed tumors expressed E7, were killed in vitro by T cells from vaccinated mice, and had changes in IL-6, TGFβ, TNFα, and p53 that were not causative of resistance. Vaccination of naive hosts bearing tumor cells from relapsed tumors did not induce regression despite CD8+ T cell infiltration. Attracting inflammatory myeloid effector cells, which non-responding lesions from HPV16-vaccinated patients lacked, restored vaccine response.
Contributed by Paula Hochman
BACKGROUND: Immunotherapy of cancer is successful but tumor regression often is incomplete and followed by escape. Understanding the mechanisms underlying this acquired resistance will aid the development of more effective treatments. METHODS: We exploited a mouse model where tumor-specific therapeutic vaccination results in tumor regression, followed by local recurrence and resistance. In depth studies on systemic, local and tumor intrinsic changes were performed with flow and mass cytometry, immunohistochemistry, transcriptomics and several perturbation studies with inhibitors or agonistic antibodies in mice. Main findings were recapitulated in vaccinated patients. RESULTS: Full tumor regression and cure of tumor-bearing mice is dependent on the magnitude of the vaccine-induced T-cell response. Recurrence of tumors did not involve classical immune escape mechanisms, such as antigen-presentation alterations, immune checkpoint expression, resistance to killing or local immune suppression. However, the recurrent tumors displayed a changed transcriptome with alterations in p53, tumor necrosis factor-_ and transforming growth factor-_ signaling pathways and they became immunologically cold. Remarkably, ex vivo cell-sorted recurrent tumors, directly reinjected in nave hosts retained their resistance to vaccination despite a strong infiltration with tumor-specific CD8(+) T cells, similar to that of vaccine-responsive tumors. The influx of inflammatory mature myeloid effector cells in the resistant tumors, however, was impaired and this turned out to be the underlying mechanisms as restoration of inflammatory myeloid cell infiltration reinstated the sensitivity of these refractory tumors to vaccination. Notably, impaired myeloid cell infiltration after vaccination was also associated with vaccine resistance in patients. CONCLUSION: An immunotherapy-induced disability of tumor cells to attract innate myeloid effector cells formed a major mechanism underlying immune escape and acquired resistance. These data not only stresses the importance of myeloid effector cells during immunotherapy but also demands for new studies to harness their tumoricidal activities.
Author Info: (1) Oncode institute, Medical Oncology, Leiden University Medical Center, Leiden, The Netherlands. (2) Oncode institute, Medical Oncology, Leiden University Medical Center, Leiden,
Author Info: (1) Oncode institute, Medical Oncology, Leiden University Medical Center, Leiden, The Netherlands. (2) Oncode institute, Medical Oncology, Leiden University Medical Center, Leiden, The Netherlands. (3) Oncode institute, Medical Oncology, Leiden University Medical Center, Leiden, The Netherlands. (4) Oncode institute, Medical Oncology, Leiden University Medical Center, Leiden, The Netherlands. (5) Pathology, Leiden University Medical Center, Leiden, The Netherlands. (6) Oncode institute, Medical Oncology, Leiden University Medical Center, Leiden, The Netherlands. (7) Immunohematology and Bloodtransfusion, Leiden Universitair Medisch Centrum, Leiden, The Netherlands. (8) Immunohematology and Bloodtransfusion, Leiden Universitair Medisch Centrum, Leiden, The Netherlands. (9) Cell and Chemical Biology, Leiden University Medical Center, Leiden, The Netherlands. (10) Cell and Chemical Biology, Leiden University Medical Center, Leiden, The Netherlands. (11) Pathology, Leiden University Medical Center, Leiden, The Netherlands. (12) Pathology, Leiden University Medical Center, Leiden, The Netherlands. (13) Oncode institute, Medical Oncology, Leiden University Medical Center, Leiden, The Netherlands. (14) Immunohematology and Bloodtransfusion, Leiden Universitair Medisch Centrum, Leiden, The Netherlands. (15) Oncode institute, Medical Oncology, Leiden University Medical Center, Leiden, The Netherlands shvdburg@lumc.nl.
