Abstract 908
Background
Romidepsin (FK228), a histone deacetylase inhibitor (HDACi), has anti-tumor effects against several types of solid tumors. Studies have suggested that HDACi could upregulate PD-L1 expression in tumor cells, changing the state of anti-tumor immune responses. However, the influence of enhanced PD-L1 expression in tumor cells induced by romidepsin on anti-tumor immune responses are still under debate. So, the purpose of this study was to explore the anti-tumor effects and influence on immune responses of romidepsin in colon cancer.
Methods
The effects of romidepsin on proliferation, cell cycle and apoptosis in the murine colon cancer cell lines CT26 and MC38 were evaluated. PD-L1 expression levels were examined before and after treatment with romidepsin. To analyze the mechanisms through which romidepsin regulates PD-L1 expression, the acetylation of histones H3 and H4 and transcription factor BRD4 was measured. The influence of romidepsin on FOXP3+ regulatory T cells (Tregs), Th1/Th2 balance and IFN-γ+CD8+ T cells was evaluated in a subcutaneous transplanted tumor model and a colitis-associated cancer (CAC) model.
Results
The results indicated that romidepsin inhibited proliferation, induced G0/G1 cell cycle arrest and increased apoptosis in CT26 and MC38 cells. Romidepsin treatment increased PD-L1 expression in CT26 and MC38 cells via increasing the acetylation levels of histones H3 and H4 and regulating the transcription factor BRD4. In subcutaneous transplant tumor mice and CAC mice, romidepsin increased the percentage of FOXP3+ Tregs, decreased the ratio of Th1/Th2 cells and decreased the percentage of IFN-γ+CD8+ T cells in the peripheral blood and the tumor microenvironment. Upon combination with an anti-PD-1 antibody, the anti-tumor effects were enhanced, and the influence on CD4+ and CD8+ T cells was partially reversed.
Conclusions
Although romidepsin had direct anti-tumor effects in murine colon cancer, it increased PD-L1 expression in tumor cells and the percentage of immune-suppressive cells. Combination with anti-PD-1 antibody augmented the anti-tumor effects by reversing the influence of romidepsin on immune cells.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
The author.
Funding
National Natural Science Foundation of China.
Disclosure
The author has declared no conflicts of interest.
Resources from the same session
5295 - Predictive factors and survival outcomes with stereotactic body radiation therapy in treatment of oligometastases in colorectal cancer
Presenter: Vibhay Pareek
Session: Poster Display session 2
Resources:
Abstract
5887 - Factors of importance in procuring tumoroids from colorectal liver metastasis biopsies for precision medicine.
Presenter: Lars Henrik Jensen
Session: Poster Display session 2
Resources:
Abstract
2196 - FUSAFE individual patient data meta-analysis (MA) to assess the performance of dihydropyrimidine dehydrogenase (DPD) gene polymorphisms for predicting grade 4-5 fluoropyrimidine (FP) toxicity
Presenter: Marie-Christine Etienne-Grimaldi
Session: Poster Display session 2
Resources:
Abstract
2859 - Treatments (tx) after progression to first-line FOLFOXIRI + bevacizumab (bev) in metastatic colorectal cancer (mCRC) patients (pts): A pooled analysis of TRIBE and TRIBE-2 studies by GONO.
Presenter: Daniele Rossini
Session: Poster Display session 2
Resources:
Abstract
3888 - Randomized phase III study of sequential treatment with capecitabine or 5-fluorouracil (FP) plus bevacizumab (BEV) followed by the addition with oxaliplatin (OX) versus initial combination with OX+FP+ BEV in the first-line chemotherapy for metastatic colorectal cancer: The C-cubed study
Presenter: Takeshi Nagasaka
Session: Poster Display session 2
Resources:
Abstract
1065 - Early tumour shrinkage (ETS), depth of response (DpR) and associated survival outcomes in patients (pts) with RAS wild type (WT) metastatic colorectal cancer (mCRC) classified according to Köhne prognostic category: retrospective analysis of the panitumumab (Pmab) PRIME study
Presenter: Andrea Sartore-Bianchi
Session: Poster Display session 2
Resources:
Abstract
1702 - Randomized phase II trial of CAPOX with planned oxaliplatin stop-and-go strategy as adjuvant chemotherapy after curative resection of colon cancer (CCOG-1302 study)
Presenter: Hiroyuki Yokoyama
Session: Poster Display session 2
Resources:
Abstract
5104 - A metabolomic recurrence score for risk-stratification of elderly patients (pts) with early colorectal cancer (eCRC)
Presenter: Samantha Di Donato
Session: Poster Display session 2
Resources:
Abstract
5285 - RAS mutant allele fraction in plasma predicts benefit to anti-angiogenic based first line treatment in metastatic colorectal cancer
Presenter: Giulia Martini
Session: Poster Display session 2
Resources:
Abstract
1790 - Impact of prophylactic systemic antibiotics (SA) on outcome of patients (pts) with RAS-wildtype (RAS-wt) metastatic colorectal carcinoma (mCRC) treated with cetuximab-based first-line therapy. Subgroup analysis of the german non-interventional study ERBITAG
Presenter: Stephan Sahm
Session: Poster Display session 2
Resources:
Abstract