Decitabine induces <i>IRF7</i>-mediated immune responses in p53-mutated triple-negative breast cancer: a clinical and translational study

doi:10.1007/s11684-023-1016-8

2024, Vol. 18

Issue (2) : 357-374 https://doi.org/10.1007/s11684-023-1016-8

Decitabine induces IRF7-mediated immune responses in p53-mutated triple-negative breast cancer: a clinical and translational study

Haoyu Wang¹, Zhengyuan Wang², Zheng Wang¹, Xiaoyang Li³, Yuntong Li², Ni Yan², Lili Wu², Ying Liang², Jiale Wu², Huaxin Song², Qing Qu¹, Jiahui Huang¹, Chunkang Chang⁴, Kunwei Shen¹(

), Xiaosong Chen¹(

), Min Lu²(

)

¹. Department of General Surgery, Comprehensive Breast Health Center, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
². Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine (Shanghai), Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
³. Department of Hematology, Shanghai Institute of Hematology, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
⁴. Department of Hematology, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, Shanghai 200025, China

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Abstract

p53 is mutated in half of cancer cases. However, no p53-targeting drugs have been approved. Here, we reposition decitabine for triple-negative breast cancer (TNBC), a subtype with frequent p53 mutations and extremely poor prognosis. In a retrospective study on tissue microarrays with 132 TNBC cases, DNMT1 overexpression was associated with p53 mutations (P = 0.037) and poor overall survival (OS) (P = 0.010). In a prospective DEciTabinE and Carboplatin in TNBC (DETECT) trial (NCT03295552), decitabine with carboplatin produced an objective response rate (ORR) of 42% in 12 patients with stage IV TNBC. Among the 9 trialed patients with available TP53 sequencing results, the 6 patients with p53 mutations had higher ORR (3/6 vs. 0/3) and better OS (16.0 vs. 4.0 months) than the patients with wild-type p53. In a mechanistic study, isogenic TNBC cell lines harboring DETECT-derived p53 mutations exhibited higher DNMT1 expression and decitabine sensitivity than the cell line with wild-type p53. In the DETECT trial, decitabine induced strong immune responses featuring the striking upregulation of the innate immune player IRF7 in the p53-mutated TNBC cell line (upregulation by 16-fold) and the most responsive patient with TNBC. Our integrative studies reveal the potential of repurposing decitabine for the treatment of p53-mutated TNBC and suggest IRF7 as a potential biomarker for decitabine-based treatments.

Keywords p53 mutation triple-negative breast cancer decitabine DNMT1 IRF7 innate immune response

Corresponding Author(s): Kunwei Shen,Xiaosong Chen,Min Lu

Just Accepted Date: 20 October 2023 Online First Date: 25 December 2023 Issue Date: 27 May 2024

Cite this article:

Haoyu Wang,Zhengyuan Wang,Zheng Wang, et al. Decitabine induces IRF7-mediated immune responses in p53-mutated triple-negative breast cancer: a clinical and translational study[J]. Front. Med., 2024, 18(2): 357-374.

URL:

https://academic.hep.com.cn/fmd/EN/10.1007/s11684-023-1016-8
https://academic.hep.com.cn/fmd/EN/Y2024/V18/I2/357

Fig.1 DNMT1 overexpression was associated with p53 mutation and poor prognosis in TNBC. (A) Integrated heatmap of biomarkers (IHC of p53, DNMT1, DNMT3A, DNMT3B, and 5mC), clinicopathological features and prognosis in the TMA cohort consisting of 132 patients with stage I–III TNBC. (B) Box plots of the IHC scores of DNMT1, DNMT3A, DNMT3B, and 5mC in tumors with different p53 IHC patterns. WT, wild-type p53 staining pattern; MUT, mutant p53 staining pattern. (C) Representative IHC of adjacent sections showing scattered, absent, or diffused p53 and DNMT1 staining patterns. (D) Kaplan–Meier plots of RFS and OS stratified by DNMT1 expression levels. HR, hazard ratio; CI, confidence interval. (E) Forest plot of multivariate regression models predicting RFS and OS by combining biomarkers and clinicopathological features. Statistically significant features are marked in red. (F) Kaplan–Meier plots of RFS and OS for p53-mutated patients stratified by DNMT1 expression levels. (G) Forest plot of multivariate regression models predicting RFS and OS by combining biomarkers and clinicopathological features in p53-mutated patients. Statistically significant features are marked in red.

Fig.2 Response and AEs in the DETECT trial. (A) Eligibility, treatment design, and endpoints of the DETECT trial. (B) Swimmer plot illustrating the best response, PFS (progression-free survival), postprogression survival (PPS), and survival status of each patient. PD, progressed disease; SD, stable disease; PR, partial response. (C) Waterfall plot illustrating the best response of the 12 trialed patients during treatment. (D) Spider plot demonstrating the size changes in the targeted lesions from the baseline every 2 treatment cycles. (E) Representative radiological images showing changes in the targeted lesions of patients #10 and #6. Targeted lesions are marked with red circles. Pt, patient. (F and G) Kaplan–Meier plots of the PFS and OS of patients enrolled in DETECT. The median survival time is shown. (H) Observed hematological and nonhematological AEs and number of treatment cycles for the 12 trialed patients. Upper panel showing the observed hematological and nonhematological AEs. The number of treatment cycles for the 12 trialed patients is shown in the lower panel.

Tab.1 Demographics and baseline characteristics of patients enrolled in the DETECT trial

Tab.2 Summary of AEs

Fig.3 Correlation between p53 mutations and responses in the DETECT trial. (A) DNA demethylation of PBMCs from Pt #10, #11, and #12. Pt, patient. PBMCs were collected and gDNA was extracted. The representative LINE-1 methylation levels were determined. The right panel shows the quantified LINE-1 methylation levels. (B) Location of the 6 p53 mutations identified in the DETECT trial. (C) Swimmer plot illustrating the best response, PFS, PPS, and survival status of patients with different p53 mutation statuses and DNMT1 expression levels. (D) Waterfall plot illustrating the best response among the trialed patients with different p53 mutation statuses. Wild-type p53 is marked in blue, mutant p53 in orange, and primary tumor tissues unavailable for sequencing are in gray. (E) Spider plot demonstrating the size changes of the targeted lesions with different p53 mutation statuses from the baseline at every 2 treatment cycles. Wild-type p53 is marked in blue, mutant p53 is in orange, and primary tumor tissues unavailable for sequencing are in gray. (F and G) Kaplan–Meier plots showing PFS and OS stratified by p53 mutation status. The median survival time of each subgroup is shown. (H) Waterfall plot illustrating the best response in the trialed patients with different DNMT1 expression levels. High DNMT1 expression is marked in dark green, low DNMT1 expression is marked in light green, and primary tumor tissues unavailable for sequencing are in gray. (I) Spider plot demonstrating the size changes in the targeted lesions with different DNMT1 expression levels from the baseline at every 2 treatment cycles. High DNMT1 high expression is marked in dark green, low DNMT1 expression is marked in light green, and primary tumor tissues unavailable for sequencing are in gray. (J and K) Kaplan–Meier plots showing PFS and OS stratified by different DNMT1 expression levels. The median survival time of each subgroup is shown.

Fig.4 Decitabine preferentially inhibited isogenic TNBC cell lines harboring DETECT-derived p53 mutations. (A) Left panel showing the structural view of the DBD of wild-type p53 (3KMD, chain A) with the 4 residues of interest and 2 representative DNA-contacting residues shown as yellow and brown sticks, respectively. The solvent-accessible surface area of the indicated residues was calculated by PyMOL and shown. Right panel, the interaction networks of the 4 residues of interest with the involved hydrogen bonds shown as dotted lines. (B) Luciferase reporter assay indicating the transcriptional activity of the indicated p53 mutants on CDKN1A in p53-null H1299 cells. (C) Immunoblotting of DNMT1, DNMT3A, and DNMT3B in the TNBC cell line HCC1937 after treatment with a concentration gradient of decitabine. (D) Relative mRNA levels of DNMT1 in isogenic HCC1937 cell lines infected with wild-type p53 and DETECT-derived p53 mutants. (E) Protein levels of DNMT1 in isogenic HCC1937 cell lines expressing DETECT-derived p53 mutations. p21 was used as the control for the functional wild-type p53. (F) Luciferase reporter assay on the transcriptional activity of wild-type p53 on DNMT1 and CDKN1A promoters in p53-null H1299 cells. (G) Relative mRNA levels of DNMT1 and CDKN1A in p53-null HCC1937 cells transfected with the vector, wild-type p53, p53-L25Q/W26S (p53^25,26), or p53-L25Q/W26S/F53Q/F54S (p53^25,26,53,54). (H) Immunoblotting of DNMT1 and CDKN1A in HCC1937 cells transfected with the vector, wild-type p53, p53^25,26, or p53^25,26,53,54. (I) Isogenic HCC1937 cell lines were treated with different doses of decitabine every 24 h for 5 days then subjected to cell viability determination. (J) HCC1937 and BT549 cell lines were transfected with nontarget RNAi or DNMT1 RNAi. The protein levels of DNMT1 were then determined. (K) HCC1937 and BT549 cell lines transfected with nontarget RNAi or DNMT1 RNAi were treated with different doses of decitabine for 5 days and then subjected to cell viability determination. HCC1937 is marked in yellow and BT549 is marked with purple bars.

Fig.5 Decitabine potently induced IRF7-mediated immune responses in p53-deficient TNBC. (A) mRNA was isolated from p53-R282W-harboring HCC1937 cells with or without 0.3 μM decitabine treatment for 5 days then subjected to RNA-seq. Dot plot showing the FPKM values of the transcriptomes of the indicated cells. Orange dots, upregulated DEGs (fold change > 2, Gfold > 0.3). Blue dots, downregulated DEGs (fold change < 0.5, Gfold < −0.3). Gray dots, other genes classified as not differentially expressed. (B and C) Enrichment assays based on the Gene Ontology biological process and REACTOME for the 870 decitabine-upregulated DEGs as in (A). DEG numbers for each term were marked with green dots. Asterisks represent items involved in immune response. expre., expression; signal., signaling. (D) Bar plots showing the ratio of upregulated DEGs in the indicated terms and the ratio of upregulated DEGs in the whole genome. (E) Heatmap showing the expression profiles of the 613 IRGs recorded in the ImmPort database in the indicated cells. The myeloid malignant cell line Thp-1 harboring p53-R282W was included for comparison. The genes of interest are labeled. (F) Dot plot showing the fold change of the mRNA levels of the 613 IRGs upon decitabine treatment in the indicated cell lines. The genes of interest were labeled. Orange dots, IRGs preferentially upregulated in HCC1937. Blue dots, IRGs preferentially upregulated in Thp-1. Black dots, IRGs regulated in 2 cell lines. Gray dots, other unclassified IRGs. (G) PPI network for the decitabine-upregulated IRGs in HCC1937 cells based on the STRING database with MCL algorithms. Right panel showing the cluster of the specific PPI network of interest. (H) Volcano plot of the correlations between the immune cell infiltration score determined by using the ssGSEA algorithm and the expression level of IRF7 mRNA in the TNBC cohort in TCGA. Yellow circles mark immune cell types with correlation coefficients of 0.3–0.5 and red circles mark those with coefficients > 0.5. (I) Scatter plots of immune cell infiltration scores for the indicated immune cell types against the mRNA level of IRF7 in the TCGA TNBC cohort as in (G). (J) Hematoxylin and eosin staining and IRF7 and CD8 IHC staining of tumor tissues from the patient with the best response (#10) before treatment (cycle 1 day 0) and after 6 cycles of treatment.

Fig.6 Summary of the study. Left panel, in the retrospective TMA study, DNMT1 overexpression was associated with p53 mutation and poor OS in TNBC. Middle panel, in the prospective DETECT trial on the combination of decitabine and carboplatin in 12 patients with metastatic stage IV TNBC, an ORR of 42% was achieved, wherein patients with p53-mutated TNBC preferentially benefited (ORR 3/6 vs. 0/3). Right panel, in the matched mechanistical study on isogenic TNBC cell lines, DETECT-derived p53 mutations conferred TNBC cells with sensitivity to decitabine treatment by upregulating DNMT1. Compared with the treatment for myeloid malignancy, decitabine potently induced innate immune response featuring striking IRF7 upregulation and consequent T cell activation in p53-mutated TNBC cell lines and the best patient response in DETECT trial. upreg., upregulation; pre-treat., pre-treatment; post-treat., post-treatment.

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[1]	Hongnan Mo, Binghe Xu. Progress in systemic therapy for triple-negative breast cancer[J]. Front. Med., 2021, 15(1): 1-10.

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