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SARS-CoV-2 receptor ACE2 identifies immuno-hot tumors in breast cancer

10 May 2021-bioRxiv (Cold Spring Harbor Laboratory)-
TL;DR: In this article, a systematic pan-cancer analysis was conducted to assess the expression pattern and immunological role of ACE2 based on RNA-sequencing (RNA-seq) data downloaded from The Cancer Genome Atlas (TCGA).
Abstract: Angiotensin-converting enzyme 2 (ACE2) is known as a host cell receptor for Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), which is identified to be dysregulated in multiple tumors. Although the characterization of abnormal ACE2 expression in malignancies has been preliminarily explored, in-depth analysis of ACE2 in breast cancer (BRCA) has not been elucidated. A systematic pan-cancer analysis was conducted to assess the expression pattern and immunological role of ACE2 based on RNA-sequencing (RNA-seq) data downloaded from The Cancer Genome Atlas (TCGA). Next, correlations between ACE2 expression immunological characteristics in the BRCA tumor microenvironment (TME) were evaluated. Also, the role of ACE2 in predicting the clinical features and the response to therapeutic options in BRCA was estimated. These findings were subsequently validated in another public transcriptomic cohort as well as a recruited cohort. ACE2 was lowly expressed in most cancers compared with adjacent tissues. ACE2 was positively correlated with immunomodulators, tumor-infiltrating immune cells (TIICs), cancer immunity cycles, immune checkpoints, and tumor mutation burden (TMB). Besides, high ACE2 levels indicated the triple-negative breast cancer (TNBC) subtype of BRCA, lower response to endocrine therapy and higher response to chemotherapy, anti-ERBB therapy, antiangiogenic therapy and immunotherapy. To sum up, ACE2 correlates with an inflamed TME and identifies immuno-hot tumors, which may be used as an auxiliary biomarker for the identification of immunological characteristics in BRCA.

Summary (2 min read)

Introduction

  • Coronavirus disease 2019 (COVID-19) is infectious pneumonia caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection [1].
  • Thus, organs expressing high ACE2 appear to be more impressionable to SARS-CoV-2 infection in healthy individuals.
  • Cold tumors are characterized as immunosuppressive TME and insensitive to either chemotherapy or immunotherapy, and hot tumors represent higher response rates to these therapies, which is featured by T cell infiltration and immunosuppressive TME [14].
  • The authors discovered that ACE2 exhibited the tightest correlation with immunological factors in BRCA, which may be a dominant tumor species for the in-depth analysis of the immunological role of ACE2.

Public datasets retrieval

  • The pan-cancer normalized RNA-seq datasets, copy number variant (CNV) data processed by GISTIC algorithm, 450K methylation data, mutation profiles, the activities of transcription factor (TF) calculated by RABIT, and clinical information were obtained from UCSC Xena data portal (https://xenabrowser.net/datapages/).
  • Prognostic analysis using PrognoScan PrognoScan database (http://dna00.bio.kyutech.ac.jp/PrognoScan/) was applied to assess the prognostic value of ACE2 in BRCA across a large cohort of public microarray datasets [17].
  • All the results were exhibited in the study.
  • ESTIMATE algorithm was also performed to calculate Tumor Purity, ESTIMATE Score, Immune Score and Stromal Score [26].
  • Furthermore, the authors also collected several well-known effector genes of TIICs, and computed the T cell inflamed score according to the expression levels and weighting coefficient of 18 genes reported by Ayer et al. [27].

Immunophenoscore analysis

  • As previously reported, a patient’s immunophenoscore (IPS) can be calculated without bias using machine learning by consideration of the 4 major categories of components that measure immunogenicity: effector cells, immunosuppressive cells, MHC molecules, and immunomodulators [19].
  • The IPS values of BRCA patients were obtained from the Cancer Immunome Atlas (TCIA) (https://tcia.at/home).
  • Calculation of the enrichment scores of various gene signatures According to previous research [28], the authors collected several gene-sets positively associated with therapeutic response to immunotherapy, targeted therapy and radiotherapy, and specific markers of biological process correlated with anti-tumor immunity such as genes involved in DNA replication.
  • The enrichment scores of these signatures were obtained using the GSVA R package [29].

Prediction of therapeutic response

  • The role of ACE in predicting the response to chemotherapy was also evaluated.
  • First, BRCA-related drug-target genes were screened using the Drugbank database (https://go.drugbank.com/).
  • Several common therapeutics, including vinblastine, cisplatin, doxorubicin, etoposide, gefitinib, gemcitabine, paclitaxel, parthenolide, sunitinib and vinorelbine were selected.
  • The prediction process was performed by R package “pRRophetic” where the samples’ half-maximal inhibitory concentration (IC50) was calculated by ridge regression and the prediction accuracy was assessed by 10-fold cross-validation according to the CGP training set.
  • Default options were used for all parameters [30].

Clinical samples

  • Two tissue microarrays (TMAs, HBreD050Bc01 and HBreD090Bc03) were obtained from Outdo Biotech (Shanghai, China).
  • The HBreD050Bc01 microarray contained 40 BRCA and 10 adjacent samples.
  • The HBreD090Bc03 microarray contained 85 BRCA and 5 adjacent samples.
  • Thus, a total of 125 BRCA samples and 15 adjacent samples were involved in the current research.

Immunohistochemistry and semi-quantitative evaluation

  • Next, Immunohistochemistry (IHC) staining was conducted on these tissue slides.
  • Antibody staining was visualized with DAB and hematoxylin counterstain, and stained sections were scanned using Aperio Digital Pathology Slide Scanners.
  • All stained sections were independently evaluated by two independent pathologists.
  • The immunoreactivity score (IRS) equals to the percentages of positive cells multiplied with staining intensity.

Statistical analysis

  • Statistical analysis and figure exhibition performed using R language 4.0.0.
  • The statistical difference of continuous variables between the two groups was evaluated by Wilcoxon rank sum test or Mann-Whitney test and chi-square test was used when the categorical variables were assessed.
  • Pearson’s correlation was used to evaluete the correlation between two variables.
  • Receiver-operating characteristic (ROC) analysis was plotted to assess the specificity and sensitivity of the candidate indicator, and the area under the ROC curve (AUC) was generated for diagnostic biomarkers.
  • Prognostic values of categorical variables were assessed by log-rank test.

Results

  • Expression and immunological roles of ACE2 across human cancers.
  • In their research, ACE2 was suggested to be positively related to most immune checkpoints, including VTCN1, PD-L1, PD-1, CTLA4 and so on .
  • As Figure 4A exhibited, ACE2 expression was significantly associated with age, histological type, molecular type, ER status and PR status, but not related to other features.
  • To further validate above results, the authors also obtained a TMA cohort for verification, which included 125 BRCA samples and 15 adjacent samples.
  • In conclusion, ACE2 expression is related to clinical features and immune phenotypes in BRCA.

Discussion

  • COVID-19 is becoming a global concern and the major public threat in the last two years.
  • Besides, cancer patients have a worse prognosis after SARS-CoV-2 infection.
  • Thus, the authors speculated SARS‐CoV‐2 infection induced spontaneous remission of tumor has parallels with oncolytic virotherapy to some extent.
  • Besides, the associations between ACE2 with anti-tumor immunity and immunotherapy were also explored.
  • PD-L1 was often overexpressed in TNBC [46], and its response to immune checkpoint inhibition was encouraging.

Conclusions

  • In the current study, the authors revealed that ACE2 shaped an inflamed TME according to the evidence that ACE2 positively related to the immunological patterns of TME in BRCA.
  • Besides, the authors uncovered that BRCA had the potential to estimate the response of immunotherapy, the molecular subtypes and the response to several therapeutic strategies.
  • Overall, ACE2 may be used as a promising biomarker for the identification of immunological features in BRCA.

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Title: SARS-CoV-2 receptor ACE2 identifies immuno-hot tumors in breast cancer
Running title: ACE2 identifies immuno-hold tumors
Author list:
Jie Mei
1,2,*
, Yun Cai
1,2,*
, Rui Xu
2,*
, Xinqian Yu
3,*
, Lingyan Chen
1
, Tao Ma
4
, Tianshu
Gao
2
, Fei Gao
2
, Yichao Zhu
3,5,#
, Yan Zhang
1,#
Note: Jie Mei, Yun Cai, Rui Xu and Xinqian Yu contributed equally to this work
Authors’ affiliations:
1 Department of Oncology, Wuxi Maternal and Child Health Hospital Affiliated to
Nanjing Medical University, Wuxi 214000, China.
2 Wuxi Clinical Medical College, Nanjing Medical University, Wuxi 214000, China.
3 Department of Physiology, Nanjing Medical University, Nanjing 211166, China.
4 Department of Breast Surgery, Wuxi Maternal and Child Health Hospital Affiliated
to Nanjing Medical University, Wuxi 214000, China.
5 State Key Laboratory of Reproductive Medicine, Nanjing Medical University,
Nanjing 211166, China.
E-mails for Authors:
Jie Mei: meijie1996@njmu.edu.cn
Yun Cai: kellie_cai@163.com
Rui Xu: xurui@njmu.edu.cn
Xinqian Yu: xqyu0507@sina.com
Lingyan Chen: chenlingyan9711@163.com
Tao Ma: mataowx@sina.com
Tianshu Gao: gtsh0115@163.com
Fei Gao: gf2017068397@163.com
Yichao Zhu: zhuyichao@njmu.edu.cn
.CC-BY-NC-ND 4.0 International licensemade available under a
(which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is
The copyright holder for this preprintthis version posted May 10, 2021. ; https://doi.org/10.1101/2021.05.10.443377doi: bioRxiv preprint

Yan Zhang: fuyou2007@126.com
# Corresponding author:
Yan Zhang, Ph. D
Department of Oncology
Wuxi Maternal and Child Health Hospital Affiliated to Nanjing Medical University
No. 48 Huaishu Rd., Wuxi 214000, China
E-mail: fuyou2007@126.com
# Corresponding author:
Yichao Zhu, Ph. D
Department of Physiology
Nanjing Medical University
No. 101 Longmian Av., Nanjing 211166, China
E-mail: zhuyichao@njmu.edu.cn
.CC-BY-NC-ND 4.0 International licensemade available under a
(which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is
The copyright holder for this preprintthis version posted May 10, 2021. ; https://doi.org/10.1101/2021.05.10.443377doi: bioRxiv preprint

Abstract
Angiotensin-converting enzyme 2 (ACE2) is known as a host cell receptor for Severe
Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), which is identified to be
dysregulated in multiple tumors. Although the characterization of abnormal ACE2
expression in malignancies has been preliminarily explored, in-depth analysis of ACE2
in breast cancer (BRCA) has not been elucidated. A systematic pan-cancer analysis was
conducted to assess the expression pattern and immunological role of ACE2 based on
RNA-sequencing (RNA-seq) data downloaded from The Cancer Genome Atlas
(TCGA). Next, correlations between ACE2 expression immunological characteristics
in the BRCA tumor microenvironment (TME) were evaluated. Also, the role of ACE2
in predicting the clinical features and the response to therapeutic options in BRCA was
estimated. These findings were subsequently validated in another public transcriptomic
cohort as well as a recruited cohort. ACE2 was lowly expressed in most cancers
compared with adjacent tissues. ACE2 was positively correlated with
immunomodulators, tumor-infiltrating immune cells (TIICs), cancer immunity cycles,
immune checkpoints, and tumor mutation burden (TMB). Besides, high ACE2 levels
indicated the triple-negative breast cancer (TNBC) subtype of BRCA, lower response
to endocrine therapy and higher response to chemotherapy, anti-ERBB therapy,
antiangiogenic therapy and immunotherapy. To sum up, ACE2 correlates with an
inflamed TME and identifies immuno-hot tumors, which may be used as an auxiliary
biomarker for the identification of immunological characteristics in BRCA.
Key words: ACE2, breast cancer, tumor immunity, tumor microenvironment
.CC-BY-NC-ND 4.0 International licensemade available under a
(which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is
The copyright holder for this preprintthis version posted May 10, 2021. ; https://doi.org/10.1101/2021.05.10.443377doi: bioRxiv preprint

Introduction
Coronavirus disease 2019 (COVID-19) is infectious pneumonia caused by Severe
Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection [1]. At the end
of 2019, COVID-19 was originally reported in China in December 2019. Just over a
year, COVID-19 has transmitted fastly to almost all countries, which leads to a serious
global public health problem. Based on the latest statistics released by World Health
Organization, a total of 146,054,107 confirmed cases and 3,092,410 deaths have been
reported as of 25 April, 2021 (https://covid19.who.int/). Angiotensin-converting
enzyme 2 (ACE2) is recognized as a host cell receptor for SARS-CoV and SARS-CoV-
2 [2, 3]. Emerging research reported that the expression and distribution of ACE2 were
tissue-specific to some extent, which is enriched in the lung, esophagus, kidney, bladder,
testis, stomach and ileum using a single-cell RNA sequencing (RNA-seq) technique [4].
However, ACE2 is expressed in all organs, excepting for the prostate and brain,
although some organs exhibit low expression [5]. Thus, organs expressing high ACE2
appear to be more impressionable to SARS-CoV-2 infection in healthy individuals.
Breast cancer (BRCA) is a multifactorial disease, which has the highest incidence
in the world. In 2020, a total of 2,261,419 new cases and 684,996 deaths have been
reported according to the latest statistics [6]. Be a multifactorial disease, dysregulation
of the immune landscape acts as a significant role in the oncogenesis and development
of BRCA, which lays the molecular foundation for immunotherapy [7]. ACE2 is known
as a tumor suppressor and is lowly expressed in most cancers [8-10]. Encouragingly,
several analyses reveal that ACE2 correlates with the abundances of a number of tumor-
infiltrating immune cells (TIICs) in multiple cancers [11, 12]. However, indiscriminate
pan-cancer analysis neglects in-depth research on dominant tumor species, which may
lead to ignoring the great value of ACE2 in regulating tumor immunity and acting as a
indicator for the stratification of tumor immunogenicity.
Tumors are complex masses consisting of malignant as well as normal cells. The
multiple interplays between these cells via cytokines, chemokines and growth factors
constitute the tumor microenvironment (TME) [13]. TME could be crucial for the
response to several therapies and the prognosis. Tumors can be simply classified into
.CC-BY-NC-ND 4.0 International licensemade available under a
(which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is
The copyright holder for this preprintthis version posted May 10, 2021. ; https://doi.org/10.1101/2021.05.10.443377doi: bioRxiv preprint

cold or hot depending on their TME. Cold tumors are characterized as
immunosuppressive TME and insensitive to either chemotherapy or immunotherapy,
and hot tumors represent higher response rates to these therapies, which is featured by
T cell infiltration and immunosuppressive TME [14]. In principle, the hot tumors
exhibit a good response to immunotherapy, such as anti-PD-1/PD-L1 therapy [15].
Thus, distinguishing hot and cold tumors is a critical strategy to demarcate the response
to immunotherapy.
In this research, we first conducted a pan-cancer analysis of the expression and
immunological features of ACE2. We discovered that ACE2 exhibited the tightest
correlation with immunological factors in BRCA, which may be a dominant tumor
species for the in-depth analysis of the immunological role of ACE2. We also revealed
that ACE2 indicated an inflamed TME and identified immuno-hot tumors in BRCA,
and had the potential to estimate the molecular subtype of BRCA.
Methodology
Public datasets retrieval
The Cancer Genome Atlas (TCGA) data: The pan-cancer normalized RNA-seq datasets,
copy number variant (CNV) data processed by GISTIC algorithm, 450K methylation
data, mutation profiles, the activities of transcription factor (TF) calculated by RABIT,
and clinical information were obtained from UCSC Xena data portal
(https://xenabrowser.net/datapages/). The somatic mutation data were obtained from
TCGA (http://cancergenome.nih.gov/) and then used to calculate the tumor mutation
burden (TMB) by R package “maftools”. The abbreviations for TCGA cancer types are
shown in Table S1.
METABRIC data: The normalized RNA-seq dataset, CNV data processed by
GISTIC algorithm, mutation profiles and clinical data of BRCA patients in
METABRIC cohort were downloaded from cBioPortal data portal
(http://www.cbioportal.org/datasets) [16].
Prognostic analysis using PrognoScan
.CC-BY-NC-ND 4.0 International licensemade available under a
(which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is
The copyright holder for this preprintthis version posted May 10, 2021. ; https://doi.org/10.1101/2021.05.10.443377doi: bioRxiv preprint

Citations
More filters
Journal ArticleDOI
TL;DR: The results suggested an increased risk of poor outcomes in TNBC patients with a history of SARS-CoV-2 infection, which required a long-term follow-up.
Abstract: Coronavirus disease 2019 (COVID-19) has spread faster due to the emergence of SARS-CoV-2 variants, which carry an increased risk of infecting patients with comorbidities, such as breast cancer. However, there are still few reports on the effects of SARS-CoV-2 infection on the progression of breast cancer, as well as the factors and mechanisms involved. In the present study, we investigated the impact of SARS-CoV-2 proteins on breast cancer cells (BCC). The results suggested that SARS-CoV-2 M protein induced the mobility, proliferation, stemness and in vivo metastasis of a triple-negative breast cancer (TNBC) cell line, MDA-MB-231, which are involved in the upregulation of NFκB and STAT3 pathways. In addition, compared to MDA-MB-231 cells, the hormone-dependent breast cancer cell line MCF-7 showed a less response to M protein, with the protein showing no effects of promoting proliferation, stemness, and in vivo metastasis. Of note, coculture with M protein-treated MDA-MB-231 cells significantly induced the migration, proliferation, and stemness of MCF-7 cells, which are involved in the upregulation of genes related to EMT and inflammatory cytokines. Therefore, SARS-CoV-2 infection might promote the ability of aggressive BCC to induce the malignant phenotypes of the other non-aggressive BCC. Taken together, these findings suggested an increased risk of poor outcomes in TNBC patients with a history of SARS-CoV-2 infection, which required a long-term follow-up. In addition, the inhibition of NFκB and STAT3 signaling pathways is considered as a promising candidate for the treatment of worsen clinical outcomes in TNBC patients with COVID-19.

4 citations

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Frequently Asked Questions (14)
Q1. What have the authors contributed in "Title: sars-cov-2 receptor ace2 identifies immuno-hot tumors in breast cancer running title: ace2 identifies immuno-hold tumors" ?

In this paper, a systematic pan-cancer analysis was conducted to assess the expression pattern and immunological role of ACE2 based on RNA-sequencing ( RNA-seq ) data downloaded from The Cancer Genome Atlas ( TCGA ). 

After a systematic pan-cancer analysis of the expression of ACE2 in the TCGA database, the authors discovered that ACE2 was lowly expressed in a fraction of cancers, including BRCA, KICH, and LUAD. 

an isolated case report has revealed that SARS-CoV-2 infection inducedcomplete spontaneous remission in a patient with lymphoma [42]. 

ACE2 is tightly correlated with the development of an inflamed TME, which may act as a critical role in identifying the immunogenicity of BRCA. 

Themultiple interplays between these cells via cytokines, chemokines and growth factors constitute the tumor microenvironment (TME) [13]. 

In their research, ACE2 was suggested to be positively related to most immune checkpoints, including VTCN1, PD-L1, PD-1, CTLA4 and so on (Figure 2F). 

Plentiful of statistically significant terms were found and the top 5 terms positively correlated with ACE2 expression of each analysis were retained. 

The authors speculated that the prognostic value of ACE2 may be associated with subtypes and therapeutic regimens in BRCA, which needed to be further studied. 

according to previous research, ACE2 was not expressed in immune cells, and the expression of ACE2 in bulk RNA-seq data was derived from non-immune cells in all probability, such as tumor cells in the tissues.[31] 

T cell inflamed score is developed using IFN-γ-related mRNA profiles to predict clinical response to PD-1 blockade [27], and BRCA patients in the high ACE2 group exhibited higher T cell inflamed scores (Figure 3B). 

ACE2 was upregulated in ER-negative, PR-negative and the triple-negative breast cancer (TNBC) tissues (Figure S5A), and ROC analysis indicated a notable diagnostic value in identifying these molecular subtypes (Figure S5B). 

targeted therapy suppressing these oncogenic pathways could be applied for the treatment of BRCA with high ACE2 expression. 

Using IPS as a surrogate of the response to immunotherapy, the authors discovered that patients with high ACE2 expression had notably higher IPS (Figure 3G). 

Yang et al. [12] reported that the overexpression of ACE2 was significantly associated with enhanced immune infiltration in endometrial cancer and renal papillary cell cancer.