RT Journal Article
SR Electronic
T1 Combination therapy targeting both innate and adaptive immunity improves survival in a pre-clinical model of ovarian cancer
JF Journal for ImmunoTherapy of Cancer
JO J Immunother Cancer
FD BMJ Publishing Group Ltd
SP 199
DO 10.1186/s40425-019-0654-5
VO 7
IS 1
A1 Hartl, Christina A.
A1 Bertschi, Adrian
A1 Puerto, Regina Bou
A1 Andresen, Carolin
A1 Cheney, Emily M.
A1 Mittendorf, Elizabeth A.
A1 Guerriero, Jennifer L.
A1 Goldberg, Michael S.
YR 2019
UL http://jitc.bmj.com/content/7/1/199.abstract
AB Background Despite major advancements in immunotherapy among a number of solid tumors, response rates among ovarian cancer patients remain modest. Standard treatment for ovarian cancer is still surgery followed by taxane- and platinum-based chemotherapy. Thus, there is an urgent need to develop novel treatment options for clinical translation.Methods Our approach was to analyze the effects of standard chemotherapy in the tumor microenvironment of mice harboring orthotopic, syngeneic ID8-Vegf-Defb29 ovarian tumors in order to mechanistically determine a complementary immunotherapy combination. Specifically, we interrogated the molecular and cellular consequences of chemotherapy by analyzing gene expression and flow cytometry data.Results These data show that there is an immunosuppressive shift in the myeloid compartment, with increased expression of IL-10 and ARG1, but no activation of CD3+ T cells shortly after chemotherapy treatment. We therefore selected immunotherapies that target both the innate and adaptive arms of the immune system. Survival studies revealed that standard chemotherapy was complemented most effectively by a combination of anti-IL-10, 2′3’-cGAMP, and anti-PD-L1. Immunotherapy dramatically decreased the immunosuppressive myeloid population while chemotherapy effectively activated dendritic cells. Together, combination treatment increased the number of activated T and dendritic cells as well as expression of cytotoxic factors. It was also determined that the immunotherapy had to be administered concurrently with the chemotherapy to reverse the acute immunosuppression caused by chemotherapy. Mechanistic studies revealed that antitumor immunity in this context was driven by CD4+ T cells, which acquired a highly activated phenotype. Our data suggest that these CD4+ T cells can kill cancer cells directly via granzyme B-mediated cytotoxicity. Finally, we showed that this combination therapy is also effective at delaying tumor growth substantially in an aggressive model of lung cancer, which is also treated clinically with taxane- and platinum-based chemotherapy.Conclusions This work highlights the importance of CD4+ T cells in tumor immunology. Furthermore, the data support the initiation of clinical trials in ovarian cancer that target both innate and adaptive immunity, with a focus on optimizing dosing schedules.Abbreviations:ARG1ArgininecGAMPCyclic guanosine monophosphate–adenosine monophosphatecGASCyclic GMP-AMP SynthaseChemoChemotherapyComboCombination therapyCTLA4Cytotoxic T lymphocyte–associated protein 4DEFB29Beta-defensin 29FBSFetal bovine serumFoxP3Forkhead box P3Gal3Galectin 3GZMBGranzyme BIACUCInstitutional Animal Care and Use CommitteeICOSInducible T-cell costimulatoryIFNsInterferonsITImmunotherapyLLCLewis Lung CarcinomaMDSCsMyeloid derived suppressor cellsMHCIIMajor histocompatibility complex class II moleculemm3Cubic millimetermsMedium survivalNKNatural killerPD-1Programmed death 1PD-L1Programmed death ligand 1RORγtRAR-related orphan receptor gamma 2STINGStimulator of interferon genesT-betT-box transcription factorThT helperTregRegulatory T cellVEGF-AVascular endothelial growth factor AVehVehicle