An analysis of sexual dimorphism in the tumor microenvironment of colorectal cancer

Andrea E. Geddes; Anita L. Ray; Robert A. Nofchissey; Azadeh Esmaeili; Apryl Saunders; Dawn E. Bender; Maaz Khan; Sheeja Aravindan; Jared T. Ahrendsen; Min Li; Kar Ming Fung; Muralidharan Jayaraman; Jingxuan Yang; Kristina K. Booth; Gary D. Dunn; Steven N. Carter; Katherine T. Morris

doi:10.3389/fonc.2022.986103

An analysis of sexual dimorphism in the tumor microenvironment of colorectal cancer

Andrea E. Geddes, Anita L. Ray, Robert A. Nofchissey, Azadeh Esmaeili, Apryl Saunders, Dawn E. Bender, Maaz Khan, Sheeja Aravindan, Jared T. Ahrendsen, Min Li, Kar Ming Fung, Muralidharan Jayaraman, Jingxuan Yang, Kristina K. Booth, Gary D. Dunn, Steven N. Carter, Katherine T. Morris^*

^*Corresponding author for this work

Pathology

Research output: Contribution to journal › Article › peer-review

1 Scopus citations

Abstract

Women with colorectal cancer (CRC) have survival advantages over men, yet the underlying mechanisms are unclear. T cell infiltration within the CRC tumor microenvironment (TME) correlates strongly with survival. We hypothesized that women with CRC have increased T cell infiltration and differential gene expression in the TME compared to men. Tissue microarrays comprising primary tumor, tumor infiltrated lymph nodes, and uninvolved colon were created from CRC patients. Proportions of CD4 positive (CD4+) and CD8 positive (CD8+) T cells were identified using immunohistochemistry. TME immune- and cancer-related genetic expression from primary and metastatic CRC tumor were also evaluated via the NanoStringIO360 panel and The Cancer Genome Atlas Project database. CD4+ was higher in tumor samples from women compared to men (22.04% vs. 10.26%, p=0.002) and also in lymph node samples (39.54% vs. 8.56%, p=0.001). CD8+ was increased in uninvolved colon from women compared to men (59.40% vs. 43.61%, p=0.015), and in stage I/II tumors compared to III/IV in all patients (37.01% vs. 23.91%, p=0.009). Top CD8+ tertile patients survived longer compared to the bottom (43.9 months vs. 25.3 months, p=0.007). Differential gene expression was observed in pathways related to Treg function, T cell activity, and T cell exhaustion, amongst several others, in women compared to men. Thus, significant sexual dimorphism exists in the TME that could contribute to survival advantages observed in female patients with CRC.

Original language	English (US)
Article number	986103
Journal	Frontiers in Oncology
Volume	12
DOIs	https://doi.org/10.3389/fonc.2022.986103
State	Published - Oct 28 2022

Funding

Immunohistochemistry and TMA construction services provided by the Cancer Tissue Pathology Shared Resources was supported partly by the National Institute of General Medical Sciences Grant P20GM103639 and National Cancer Institute Grant P30CA225520 of the National Institutes of Health. Research reported in this publication was supported in part by the National Cancer Institute Cancer Center Support Grant P30CA225520 awarded to the University of Oklahoma Stephenson Cancer Center and used the Laboratory of Molecular Biology and Cytometry Research and the Biospecimen and Tissue Pathology Shared Resources. In addition, the work was also supported by the University of Oklahoma Health Sciences Department of Surgery. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Keywords

T cell
colorectal cancer
immunoscore
sexual dimorphism
tumor microenvironment

ASJC Scopus subject areas

Oncology
Cancer Research

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.3389/fonc.2022.986103

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Geddes, A. E., Ray, A. L., Nofchissey, R. A., Esmaeili, A., Saunders, A., Bender, D. E., Khan, M., Aravindan, S., Ahrendsen, J. T., Li, M., Fung, K. M., Jayaraman, M., Yang, J., Booth, K. K., Dunn, G. D., Carter, S. N., & Morris, K. T. (2022). An analysis of sexual dimorphism in the tumor microenvironment of colorectal cancer. Frontiers in Oncology, 12, Article 986103. https://doi.org/10.3389/fonc.2022.986103

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title = "An analysis of sexual dimorphism in the tumor microenvironment of colorectal cancer",

abstract = "Women with colorectal cancer (CRC) have survival advantages over men, yet the underlying mechanisms are unclear. T cell infiltration within the CRC tumor microenvironment (TME) correlates strongly with survival. We hypothesized that women with CRC have increased T cell infiltration and differential gene expression in the TME compared to men. Tissue microarrays comprising primary tumor, tumor infiltrated lymph nodes, and uninvolved colon were created from CRC patients. Proportions of CD4 positive (CD4+) and CD8 positive (CD8+) T cells were identified using immunohistochemistry. TME immune- and cancer-related genetic expression from primary and metastatic CRC tumor were also evaluated via the NanoStringIO360 panel and The Cancer Genome Atlas Project database. CD4+ was higher in tumor samples from women compared to men (22.04% vs. 10.26%, p=0.002) and also in lymph node samples (39.54% vs. 8.56%, p=0.001). CD8+ was increased in uninvolved colon from women compared to men (59.40% vs. 43.61%, p=0.015), and in stage I/II tumors compared to III/IV in all patients (37.01% vs. 23.91%, p=0.009). Top CD8+ tertile patients survived longer compared to the bottom (43.9 months vs. 25.3 months, p=0.007). Differential gene expression was observed in pathways related to Treg function, T cell activity, and T cell exhaustion, amongst several others, in women compared to men. Thus, significant sexual dimorphism exists in the TME that could contribute to survival advantages observed in female patients with CRC.",

keywords = "T cell, colorectal cancer, immunoscore, sexual dimorphism, tumor microenvironment",

author = "Geddes, {Andrea E.} and Ray, {Anita L.} and Nofchissey, {Robert A.} and Azadeh Esmaeili and Apryl Saunders and Bender, {Dawn E.} and Maaz Khan and Sheeja Aravindan and Ahrendsen, {Jared T.} and Min Li and Fung, {Kar Ming} and Muralidharan Jayaraman and Jingxuan Yang and Booth, {Kristina K.} and Dunn, {Gary D.} and Carter, {Steven N.} and Morris, {Katherine T.}",

note = "Funding Information: Immunohistochemistry and TMA construction services provided by the Cancer Tissue Pathology Shared Resources was supported partly by the National Institute of General Medical Sciences Grant P20GM103639 and National Cancer Institute Grant P30CA225520 of the National Institutes of Health. Funding Information: Research reported in this publication was supported in part by the National Cancer Institute Cancer Center Support Grant P30CA225520 awarded to the University of Oklahoma Stephenson Cancer Center and used the Laboratory of Molecular Biology and Cytometry Research and the Biospecimen and Tissue Pathology Shared Resources. In addition, the work was also supported by the University of Oklahoma Health Sciences Department of Surgery. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Publisher Copyright: Copyright {\textcopyright} 2022 Geddes, Ray, Nofchissey, Esmaeili, Saunders, Bender, Khan, Aravindan, Ahrendsen, Li, Fung, Jayaraman, Yang, Booth, Dunn, Carter and Morris.",

year = "2022",

month = oct,

day = "28",

doi = "10.3389/fonc.2022.986103",

language = "English (US)",

volume = "12",

journal = "Frontiers in Oncology",

issn = "2234-943X",

publisher = "Frontiers Media S. A.",

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Geddes, AE, Ray, AL, Nofchissey, RA, Esmaeili, A, Saunders, A, Bender, DE, Khan, M, Aravindan, S, Ahrendsen, JT, Li, M, Fung, KM, Jayaraman, M, Yang, J, Booth, KK, Dunn, GD, Carter, SN & Morris, KT 2022, 'An analysis of sexual dimorphism in the tumor microenvironment of colorectal cancer', Frontiers in Oncology, vol. 12, 986103. https://doi.org/10.3389/fonc.2022.986103

TY - JOUR

T1 - An analysis of sexual dimorphism in the tumor microenvironment of colorectal cancer

AU - Geddes, Andrea E.

AU - Ray, Anita L.

AU - Nofchissey, Robert A.

AU - Esmaeili, Azadeh

AU - Saunders, Apryl

AU - Bender, Dawn E.

AU - Khan, Maaz

AU - Aravindan, Sheeja

AU - Ahrendsen, Jared T.

AU - Li, Min

AU - Fung, Kar Ming

AU - Jayaraman, Muralidharan

AU - Yang, Jingxuan

AU - Booth, Kristina K.

AU - Dunn, Gary D.

AU - Carter, Steven N.

AU - Morris, Katherine T.

N1 - Funding Information: Immunohistochemistry and TMA construction services provided by the Cancer Tissue Pathology Shared Resources was supported partly by the National Institute of General Medical Sciences Grant P20GM103639 and National Cancer Institute Grant P30CA225520 of the National Institutes of Health. Funding Information: Research reported in this publication was supported in part by the National Cancer Institute Cancer Center Support Grant P30CA225520 awarded to the University of Oklahoma Stephenson Cancer Center and used the Laboratory of Molecular Biology and Cytometry Research and the Biospecimen and Tissue Pathology Shared Resources. In addition, the work was also supported by the University of Oklahoma Health Sciences Department of Surgery. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Publisher Copyright: Copyright © 2022 Geddes, Ray, Nofchissey, Esmaeili, Saunders, Bender, Khan, Aravindan, Ahrendsen, Li, Fung, Jayaraman, Yang, Booth, Dunn, Carter and Morris.

PY - 2022/10/28

Y1 - 2022/10/28

N2 - Women with colorectal cancer (CRC) have survival advantages over men, yet the underlying mechanisms are unclear. T cell infiltration within the CRC tumor microenvironment (TME) correlates strongly with survival. We hypothesized that women with CRC have increased T cell infiltration and differential gene expression in the TME compared to men. Tissue microarrays comprising primary tumor, tumor infiltrated lymph nodes, and uninvolved colon were created from CRC patients. Proportions of CD4 positive (CD4+) and CD8 positive (CD8+) T cells were identified using immunohistochemistry. TME immune- and cancer-related genetic expression from primary and metastatic CRC tumor were also evaluated via the NanoStringIO360 panel and The Cancer Genome Atlas Project database. CD4+ was higher in tumor samples from women compared to men (22.04% vs. 10.26%, p=0.002) and also in lymph node samples (39.54% vs. 8.56%, p=0.001). CD8+ was increased in uninvolved colon from women compared to men (59.40% vs. 43.61%, p=0.015), and in stage I/II tumors compared to III/IV in all patients (37.01% vs. 23.91%, p=0.009). Top CD8+ tertile patients survived longer compared to the bottom (43.9 months vs. 25.3 months, p=0.007). Differential gene expression was observed in pathways related to Treg function, T cell activity, and T cell exhaustion, amongst several others, in women compared to men. Thus, significant sexual dimorphism exists in the TME that could contribute to survival advantages observed in female patients with CRC.

AB - Women with colorectal cancer (CRC) have survival advantages over men, yet the underlying mechanisms are unclear. T cell infiltration within the CRC tumor microenvironment (TME) correlates strongly with survival. We hypothesized that women with CRC have increased T cell infiltration and differential gene expression in the TME compared to men. Tissue microarrays comprising primary tumor, tumor infiltrated lymph nodes, and uninvolved colon were created from CRC patients. Proportions of CD4 positive (CD4+) and CD8 positive (CD8+) T cells were identified using immunohistochemistry. TME immune- and cancer-related genetic expression from primary and metastatic CRC tumor were also evaluated via the NanoStringIO360 panel and The Cancer Genome Atlas Project database. CD4+ was higher in tumor samples from women compared to men (22.04% vs. 10.26%, p=0.002) and also in lymph node samples (39.54% vs. 8.56%, p=0.001). CD8+ was increased in uninvolved colon from women compared to men (59.40% vs. 43.61%, p=0.015), and in stage I/II tumors compared to III/IV in all patients (37.01% vs. 23.91%, p=0.009). Top CD8+ tertile patients survived longer compared to the bottom (43.9 months vs. 25.3 months, p=0.007). Differential gene expression was observed in pathways related to Treg function, T cell activity, and T cell exhaustion, amongst several others, in women compared to men. Thus, significant sexual dimorphism exists in the TME that could contribute to survival advantages observed in female patients with CRC.

KW - T cell

KW - colorectal cancer

KW - immunoscore

KW - sexual dimorphism

KW - tumor microenvironment

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JO - Frontiers in Oncology

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ER -

An analysis of sexual dimorphism in the tumor microenvironment of colorectal cancer

Abstract

Funding

Keywords

ASJC Scopus subject areas

UN SDGs

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