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Pan-cancer analysis reveals homologous recombination deficiency score as a predictive marker for immunotherapy responders

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Abstract

The immune context of the tumor microenvironment (TME) is critical for effective immunotherapy. Nonetheless, DNA-based biomarkers for the immune-sensitive TME and the identification of immune checkpoint inhibitor (ICI) responders are under-explored. This study aims to comprehensively landscape the homologous recombination deficiency (HRD) score, an emerging hallmark for tumor genome instability that triggers immune responsiveness across major cancer types, and to unveil their link to the TME and immunotherapeutic response. The HRD-associated genomic scars were characterized in 9088 tumor samples across 32 cancer types from TCGA. We evaluated the HRD score’s performance in classifying ICI responders using an independent breast cancer cohort (GSE87049) and 11 in vivo murine mammary tumor models treated with anti-PD1/CTLA4 regimen (GSE124821). This study revealed a broad association between HRD-high genotype and neoantigenesis in the major cancer types including bladder cancer, breast cancer, head and neck squamous carcinoma, lung adenocarcinoma, lung squamous cell carcinoma, ovarian cancer, and sarcoma. Tumors with high HRD score bears increased leukocyte infiltration and lymphocyte fraction and demonstrated immune-sensitive microenvironment. The tumor immune dysfunction and exclusion (TIDE) model further confirmed HRD score-high genotype as a potential predictor for ICI immunotherapy responders in breast cancer. In conclusion, tumors with high HRD score exhibit an immune-sensitive TME. The HRD-high genotype is a promising marker for identifying ICI therapy responders among breast cancer patients.

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Data availability

All data generated or analyzed during this study are included in this published article (and its supplementary information files).

Abbreviations

ICI:

Immune checkpoint inhibitors

TME:

Tumor microenvironment

TMB:

Tumor mutation burden

MSI:

Microsatellite instability

GEP:

Gene expression profile

PARPi:

PARP protein inhibition

HRD:

Homologous recombination deficiency

TCGA:

The Cancer Genomic Atlas

BRCA:

Breast invasive carcinoma

CCLE:

Cancer Cell Line Encyclopedia

LOH:

Loss of heterogeneity

TAI:

Telomeric-allelic imbalance

LST:

Large-scale state transitions

DEG:

Differentially expressed gene

tSNE:

T-distributed stochastic neighbor embedding

TIDE:

Tumor immune dysfunction and exclusion

MDSC:

Myeloid-derived suppressor cell

CTL:

Cytotoxic T lymphocyte

TAM-M2:

Tumor-associated macrophages-M2

CAF:

Cancer-associated fibroblast

OV:

Ovarian serous cystadenocarcinoma

UCS:

Uterine carcinosarcoma

LUAD:

Lung adenocarcinoma

LUSC:

Lung squamous cell carcinoma

ESCA:

Esophageal carcinoma

SARC:

Sarcoma

BLCA:

Bladder urothelial carcinoma

STAD:

Stomach adenocarcinoma

HNSC:

Head and neck squamous carcinoma

PAAD:

Pancreatic ductal adenocarcinoma

PRAD:

Prostate adenocarcinoma (PRAD)

COAD:

Colon adenocarcinoma

UCEC:

Uterine corpus endometrial carcinoma

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Acknowledgements

We thank the contributions of The Cancer Genome Atlas (TCGA), Cancer Cell Line Encyclopedia (CCLE), and the National Center for Biotechnology Information Sequence Read Archive (NCBI-SRA) for providing free access to online data. We thank Dr. Anthony Brickner at the University of Pittsburgh for the language editing.

Funding

This study was supported by the National Natural Science Foundation of China [81802993, 82072367], Shanghai Municipal Key Clinical Specialty [shslczdzk03303] and the Innovation Group Project of Shanghai Municipal Health Commission [2019CXJQ03].

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Author notes

  1. Can Yang and Zijing Zhang made equal contribution.

Authors and Affiliations

  1. Department of Laboratory Medicine, Huashan Hospital, Fudan University, Shanghai, 200040, China

    Can Yang, Yuming Chen, Tingting Hu, Huating Zhang, Ming Guan & Zhiyuan Wu

  2. Department of General Surgery, Huashan Hospital, Fudan University, Shanghai, 200040, China

    Zijing Zhang

  3. Central Laboratory, Huashan Hospital North, Fudan University, Shanghai, 201907, China

    Xuemei Tang, Ming Guan & Zhiyuan Wu

  4. Central Laboratory, Huashan Hospital, Fudan University, Shanghai, 200040, China

    Xinju Zhang & Ming Guan

  5. Medical Laboratory, Shenzhen Luohu People’s Hospital, Shenzhen, 518002, China

    Xiuming Zhang

  6. Clinical Laboratory, Huashan Hospital North, Fudan University, Shanghai, 201907, China

    Ming Guan & Zhiyuan Wu

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  1. Can Yang
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Contributions

CY, XMT, XJZ, YMC, TTH, HTZ, MG, ZXM, and ZYW contributed to the study concept and design. CY, ZZJ, ZYW, and XJZ: acquisition, analysis, and validation of data; YMC, TTH and HTZ: data curation; CY, ZYW, XMT, and XJZ: drafting the manuscript and revised; MG, XMZ and WZY: supervision, project administration; MG and ZYW: funding acquisition. All the authors read and approved the final manuscript.

Corresponding authors

Correspondence to Ming Guan, Xiuming Zhang or Zhiyuan Wu.

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Conflict of interest

The authors declare no potential conflicts of interest.

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The ethical approval is not applicable as all data in this study were downloaded from public databases (TCGA, CCLE, SRA, and GEO).

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The data processing met the TCGA, CCLE, and NCBI publication guidelines.

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Not applicable.

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Yang, C., Zhang, Z., Tang, X. et al. Pan-cancer analysis reveals homologous recombination deficiency score as a predictive marker for immunotherapy responders. Human Cell 35, 199–213 (2022). https://doi.org/10.1007/s13577-021-00630-z

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  • DOI: https://doi.org/10.1007/s13577-021-00630-z

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