Abstract 3391
Background
Ovarian cancer prognosis is strongly dependent on the development of an anti-tumour immune response. However, tumours can epigenetically silence immunostimulatory genes in order to evade this response. We investigated whether a novel dual inhibitor of Ehmt2/Ezh2 methyltransferases (HKMT) was able to derepress expression of critical chemokines and augment immune responses in a murine ovarian cancer model.
Methods
ID8 Trp53-/- murine ovarian cancer cell line was previously generated, using CRISPR-Cas9 technique. Mice bearing intraperitoneal Trp53-/-tumours were treated with the novel Ehmt2/Ezh2 inhibitor, HKMTI-1-005, for 14 days (21-35d). Tumours were harvested for immune cell phenotyping by flow cytometry. HKMT1-1-005 was screened in vitrofor its ability to enhance expression of 84-chemokine genes in ID8 Trp53-/- ovarian cancer cells.
Results
In vitro, HKMTI-1-005 treatment significantly (p < 0.05) upregulated the expression of cxcl10 (3-fold), cxcl9 (22-fold) and ccl5 (14-fold), after stimulation with IFNγ. Mice treated with HKMTI-1-005 had longer survival (52 vs45d, p<.0001), less ascites (3.7 vs5.6ml, p=.0037) and trended towards tumour size reduction (weight 138 vs178mg, p=.10) compared to vehicle treatment. Tumours harvested 24hr post last HKMTI-1-005 dose had significantly more effector CD8+T cells (p=.03), natural killer (NK) cells (p<.0001) and dendritic cells (DCs, p=.02), and less naïve CD8+T cells (p=.02) and immunosuppressive CD4+Tregs (p=.02). Expression of the Cxcl9/Cxcl10 receptor Cxcr3 was increased in HKMTI-1-005-treated cohort tumours on CD8+[mean fluorescence intensity (MFI) 3959 vs2097, p<.0001], CD4+(MFI 2341 vs1099, p<.0001)and NK (MFI 1507 vs440, p<.0001) cells.
Conclusions
Inhibition of Ehmt2/Ezh2 HKMTs stimulates expression of chemokines involved in T cell, NK and DC recruitment. In vivo, HKMTI-1-005 alters the immune microenvironment and confers a small survival benefit. This suggests that HKMTI-1-005 could augment the anti-tumour immune response of current immunotherapies.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
Imperial College London.
Funding
Has not received any funding.
Disclosure
P. Spiliopoulou: Honoraria (self): BMS; Travel / Accommodation / Expenses: Nucana. I.A. McNeish: Advisory / Consultancy: Clovis Oncology; Advisory / Consultancy: Takeda; Advisory / Consultancy: Tesaro; Advisory / Consultancy: AstraZeneca; Research grant / Funding (institution): AstraZeneca. All other authors have declared no conflicts of interest.
Resources from the same session
4614 - Predictors of Response to Checkpoint Inhibitors in Naïve and Ipilimumab-Refractory Melanoma
Presenter: Domenico Mallardo
Session: Poster Display session 3
Resources:
Abstract
2901 - IFN-γ/IL-10 ratio as predictive biomarker for response to anti-PD-1 therapy in metastatic melanoma patients
Presenter: Emilio Giunta
Session: Poster Display session 3
Resources:
Abstract
2306 - Multiplex Chromogenic Immunohistochemistry (IHC) for Spatial Analysis of Checkpoint-Positive Tumor Infiltrating Lymphocytes (TILs)
Presenter: Scott Ely
Session: Poster Display session 3
Resources:
Abstract
1678 - The role of PD-L1 expression as a predictive biomarker in advanced renal cell carcinoma: a meta-analysis of randomized clinical trials.
Presenter: Alberto Carretero-Gonzalez
Session: Poster Display session 3
Resources:
Abstract
5138 - Radiomic Features as a Non-invasive Biomarker to Predict Response to Immunotherapy in Recurrent or Metastatic Urothelial Carcinoma
Presenter: Kye Jin Park
Session: Poster Display session 3
Resources:
Abstract
5800 - Integrative combination of high-plex digital profiling techniques and cluster analysis to reveal complex immune biology in the tumor microenvironment of mesothelioma
Presenter: Carmen Ballesteros-Merino
Session: Poster Display session 3
Resources:
Abstract
5736 - Predictive factors of response to immunotherapy in 198 patients with metastatic non-microcytic lung cancer (mNSCLC): real world data from 2 university hospitals in Spain
Presenter: Juan Felipe Cordoba Ortega
Session: Poster Display session 3
Resources:
Abstract
5645 - Evaluating Lung CT Density Changes Among Patients with Extensive Stage Small Cell Lung Cancer (ES-SCLC) Treated with Thoracic Radiotherapy (TRT) alone or TRT Followed by Combined Ipilimumab (IPI) and Nivolumab (NIVO).
Presenter: Kujtim Latifi
Session: Poster Display session 3
Resources:
Abstract
1540 - Immuno-oncology therapy biomarkers differences between polyoma-virus positive and negative Merkel cell carcinomas
Presenter: Zoran Gatalica
Session: Poster Display session 3
Resources:
Abstract
4538 - Can we improve patient selection for phase 1 clinical trials (Ph1) based on Immuno-Oncology score prognostic index (VIO)?
Presenter: Ignacio Matos Garcia
Session: Poster Display session 3
Resources:
Abstract