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Lymphocyte-specific kinase expression is a prognostic indicator in ovarian cancer and correlates with a prominent B cell transcriptional signature

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Abstract

Objective

To investigate the prognostic and biologic significance of immune-related gene expression in high grade serous ovarian cancer (HGSOC).

Methods

Gene expression dependent survival analyses for a panel of immune related genes were evaluated in HGSOC utilizing The Cancer Genome Atlas (TCGA). Prognostic value of LCK was validated using IHC in an independent set of 72 HGSOC. Prognostic performance of LCK was compared to cytolytic score (CYT) using RNAseq across multiple tumor types. Differentially expressed genes in LCK high samples and gene ontology enrichment were analyzed.

Results

High pre-treatment LCK mRNA expression was found to be a strong predictor of survival in a set of 535 ovarian cancers. Patients with high LCK mRNA expression had a longer median progression free survival (PFS) of 29.4 months compared to 16.9 months in those without LCK high expression (p = 0.003), and longer median overall survival (OS) of 95.1 months versus 44.5 months (p = 0.001), which was confirmed in an independent cohort by IHC (p = 0.04). LCK expression was compared to CYT across tumor types available in the TCGA and was a significant predictor of prognosis in HGSOC where CYT was not predictive. Unexpectedly, LCK high samples also were enriched in numerous immunoglobulin-related and other B cell transcripts.

Conclusions

LCK is a better prognostic factor than CYT in ovarian cancer. In HGSOC, LCK high samples were characterized by higher expression of immunoglobulin and B-cell related genes suggesting that a cooperative interaction between tumor infiltrating T and B cells may correlate with better survival in this disease.

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Abbreviations

BCR:

B cell receptor

CYT:

Cytolytic Activity Score

GZMA:

Granzyme A

HGSOC:

High grade serous ovarian cancer

LCK:

Lymphocyte specific tyrosine kinase

MHC:

Major histocompatibility complex

PRF1:

Perforin

RPPA:

Reverse phase protein array

TCGA:

The Cancer Genome Atlas

TCR:

T cell receptor

TLS:

Tertiary lymphoid structures

TMA:

Tissue microarray

TPM:

Transcripts per million

CYT:

Cytolytic Activity Score

HGSOC:

High grade serous ovarian cancer

LCK:

Lymphocyte specific tyrosine kinase

TCGA:

The Cancer Genome Atlas

TLS:

Tertiary lymphoid structures

TMA:

Tissue microarray

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Funding

This research was supported in part by the MD Anderson Cancer Center Support Grant (P30 CA016672), a T32 training grant for gynecologic oncology (CA101642; to K.H. Lu), and the Ovarian Cancer Research Program grants, Department of Defense (W81XWH-17-1-0126 and W81XWH-16-1-0038; to S.C. Mok).

Author information

Authors and Affiliations

  1. Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, 1155 Pressler St, Houston, TX, 77030, USA

    Emily Hinchcliff, Samuel C. Mok, Tsz-Lun Yeung, Qian Zhang, Melinda Yates & Amir Jazaeri

  2. Department of Pathology and Laboratory Medicine, Women and Infants Hospital of Rhode Island and The Warren Alpert Medical School of Brown University, Providence, RI, USA

    Cherie Paquette

  3. Department of Pathology, University of New Mexico, Albuquerque, NM, USA

    Sarah Kelting

  4. Department of Pathology, University of Virginia Health System, Charlottesville, VA, USA

    Mark H. Stoler

  5. Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    Jason Roszik, Weiyi Peng & Patrick Hwu

  6. The University of Texas Graduate School of Biomedical Sciences at Houston, Houston, TX, USA

    Samuel C. Mok, Melinda Yates, Patrick Hwu & Amir Jazaeri

Authors
  1. Emily Hinchcliff
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  2. Cherie Paquette
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  3. Jason Roszik
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  4. Sarah Kelting
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Contributions

EH and AJ were the principle investigators. CP, SK and MHS performed immunohistochemistry and analysis. JR helped in TCGA analysis including comparison to CYT and related statistical analyses, while WP and PH aided in research question formulation and study design. SCM, TLY, QZ, MY contributed samples and support for analysis of independent cohort. EH wrote the manuscript, on which all co-authors commented.

Corresponding author

Correspondence to Emily Hinchcliff.

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Conflict of interest

The authors declare no potential conflicts of interest.

Ethical approval and ethical standards

Independent validation cohorts were enrolled on tissue and clinical data collection protocol approved by MD Anderson Cancer Center institutional review board (IRB, protocol #: LAB06-0412). All tissue included in the tissue microarray was obtained under an IRB approved protocol at the University of Virginia (protocol #:14461).

Informed consent

Because all information from the Cancer Genome Atlas is de-identified and publically available, informed consent by the study participants and approval of an ethics committee were unnecessary to perform this portion of the analyses in this study. All patients contributing tissue were enrolled under translational protocols as listed above and consent was obtained for the use of their specimens and data for research and for publication.

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Hinchcliff, E., Paquette, C., Roszik, J. et al. Lymphocyte-specific kinase expression is a prognostic indicator in ovarian cancer and correlates with a prominent B cell transcriptional signature. Cancer Immunol Immunother 68, 1515–1526 (2019). https://doi.org/10.1007/s00262-019-02385-x

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  • DOI: https://doi.org/10.1007/s00262-019-02385-x

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