CD73 expression defines immune, molecular, and clinicopathological subgroups of lung adenocarcinoma

Pedro Rocha; Ruth Salazar; Jiexin Zhang; Debora Ledesma; Jose L. Solorzano; Barbara Mino; Pamela Villalobos; Hitoshi Dejima; Dzifa Y. Douse; Lixia Diao; Kyle Gregory Mitchell; Xiuning Le; Jianjun Zhang; Annikka Weissferdt; Edwin Parra-Cuentas; Tina Cascone; David C. Rice; Boris Sepesi; Neda Kalhor; Cesar Moran; Ara Vaporciyan; John Heymach; Don L. Gibbons; J. Jack Lee; Humam Kadara; Ignacio Wistuba; Carmen Behrens; Luisa Maren Solis

doi:10.1007/s00262-020-02820-4

CD73 expression defines immune, molecular, and clinicopathological subgroups of lung adenocarcinoma

Pedro Rocha, Ruth Salazar, Jiexin Zhang, Debora Ledesma, Jose L. Solorzano, Barbara Mino, Pamela Villalobos, Hitoshi Dejima, Dzifa Y. Douse, Lixia Diao, Kyle Gregory Mitchell, Xiuning Le, Jianjun Zhang, Annikka Weissferdt, Edwin Parra-Cuentas, Tina Cascone, David C. Rice, Boris Sepesi, Neda Kalhor, Cesar MoranAra Vaporciyan, John Heymach, Don L. Gibbons, J. Jack Lee, Humam Kadara, Ignacio Wistuba, Carmen Behrens, Luisa Maren Solis

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

15 Scopus citations

Abstract

Introduction: CD73 is a membrane-bound enzyme crucial in adenosine generation. The adenosinergic pathway plays a critical role in immunosuppression and in anti-tumor effects of immune checkpoint inhibitors (ICI). Here, we interrogated CD73 expression in a richly annotated cohort of human lung adenocarcinoma (LUAD) and its association with clinicopathological, immune, and molecular features to better understand the role of this immune marker in LUAD pathobiology. Materials and methods: Protein expression of CD73 was evaluated by immunohistochemistry in 106 archived LUADs from patients that underwent surgical treatment without neoadjuvant therapy. Total CD73 (T +) was calculated as the average of luminal (L +) and basolateral (BL +) percentage membrane expression scores for each LUAD and was used to classify tumors into three groups based on the extent of T CD73 expression (high, low, and negative). Results: CD73 expression was significantly and progressively increased across normal-appearing lung tissue, adenomatous atypical hyperplasia, adenocarcinoma in situ, minimally invasive adenocarcinoma, and LUAD. In LUAD, BL CD73 expression was associated with an increase in PD-L1 expression in tumor cells and increase of tumor-associated immune cells. Stratification of LUADs based on T CD73 extent also revealed that tumors with high expression of this enzyme overall exhibited significantly elevated immune infiltration and PD-L1 protein expression. Immune profiling demonstrated that T-cell inflammation and adenosine signatures were significantly higher in CD73-expressing lung adenocarcinomas relative to those lacking CD73. Conclusion: Our study suggests that higher CD73 expression is associated with an overall augmented host immune response, suggesting potential implications in the immune pathobiology of early stage lung adenocarcinoma. Our findings warrant further studies to explore the role of CD73 in immunotherapeutic response of LUAD.

Original language	English (US)
Pages (from-to)	1965-1976
Number of pages	12
Journal	Cancer Immunology, Immunotherapy
Volume	70
Issue number	7
DOIs	https://doi.org/10.1007/s00262-020-02820-4
State	Published - Jul 2021

Keywords

Adenosinergic pathway
CD73
Immune profiling
Lung adenocarcinoma
PD-L1

ASJC Scopus subject areas

Immunology and Allergy
Immunology
Oncology
Cancer Research

MD Anderson CCSG core facilities

Biostatistics Resource Group
Bioinformatics Shared Resource

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10.1007/s00262-020-02820-4

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Rocha, P., Salazar, R., Zhang, J., Ledesma, D., Solorzano, J. L., Mino, B., Villalobos, P., Dejima, H., Douse, D. Y., Diao, L., Mitchell, K. G., Le, X., Zhang, J., Weissferdt, A., Parra-Cuentas, E., Cascone, T., Rice, D. C., Sepesi, B., Kalhor, N., ... Solis, L. M. (2021). CD73 expression defines immune, molecular, and clinicopathological subgroups of lung adenocarcinoma. Cancer Immunology, Immunotherapy, 70(7), 1965-1976. https://doi.org/10.1007/s00262-020-02820-4

Rocha, P, Salazar, R, Zhang, J , Ledesma, D, Solorzano, JL, Mino, B, Villalobos, P, Dejima, H, Douse, DY, Diao, L, Mitchell, KG, Le, X , Zhang, J , Weissferdt, A , Parra-Cuentas, E , Cascone, T , Rice, DC, Sepesi, B, Kalhor, N , Moran, C , Vaporciyan, A , Heymach, J , Gibbons, DL , Lee, JJ , Kadara, H , Wistuba, I , Behrens, C & Solis, LM 2021, 'CD73 expression defines immune, molecular, and clinicopathological subgroups of lung adenocarcinoma', Cancer Immunology, Immunotherapy, vol. 70, no. 7, pp. 1965-1976. https://doi.org/10.1007/s00262-020-02820-4

@article{d222c14e071646aabdf452c65832f7ff,

title = "CD73 expression defines immune, molecular, and clinicopathological subgroups of lung adenocarcinoma",

abstract = "Introduction: CD73 is a membrane-bound enzyme crucial in adenosine generation. The adenosinergic pathway plays a critical role in immunosuppression and in anti-tumor effects of immune checkpoint inhibitors (ICI). Here, we interrogated CD73 expression in a richly annotated cohort of human lung adenocarcinoma (LUAD) and its association with clinicopathological, immune, and molecular features to better understand the role of this immune marker in LUAD pathobiology. Materials and methods: Protein expression of CD73 was evaluated by immunohistochemistry in 106 archived LUADs from patients that underwent surgical treatment without neoadjuvant therapy. Total CD73 (T +) was calculated as the average of luminal (L +) and basolateral (BL +) percentage membrane expression scores for each LUAD and was used to classify tumors into three groups based on the extent of T CD73 expression (high, low, and negative). Results: CD73 expression was significantly and progressively increased across normal-appearing lung tissue, adenomatous atypical hyperplasia, adenocarcinoma in situ, minimally invasive adenocarcinoma, and LUAD. In LUAD, BL CD73 expression was associated with an increase in PD-L1 expression in tumor cells and increase of tumor-associated immune cells. Stratification of LUADs based on T CD73 extent also revealed that tumors with high expression of this enzyme overall exhibited significantly elevated immune infiltration and PD-L1 protein expression. Immune profiling demonstrated that T-cell inflammation and adenosine signatures were significantly higher in CD73-expressing lung adenocarcinomas relative to those lacking CD73. Conclusion: Our study suggests that higher CD73 expression is associated with an overall augmented host immune response, suggesting potential implications in the immune pathobiology of early stage lung adenocarcinoma. Our findings warrant further studies to explore the role of CD73 in immunotherapeutic response of LUAD.",

keywords = "Adenosinergic pathway, CD73, Immune profiling, Lung adenocarcinoma, PD-L1",

author = "Pedro Rocha and Ruth Salazar and Jiexin Zhang and Debora Ledesma and Solorzano, {Jose L.} and Barbara Mino and Pamela Villalobos and Hitoshi Dejima and Douse, {Dzifa Y.} and Lixia Diao and Mitchell, {Kyle Gregory} and Xiuning Le and Jianjun Zhang and Annikka Weissferdt and Edwin Parra-Cuentas and Tina Cascone and Rice, {David C.} and Boris Sepesi and Neda Kalhor and Cesar Moran and Ara Vaporciyan and John Heymach and Gibbons, {Don L.} and Lee, {J. Jack} and Humam Kadara and Ignacio Wistuba and Carmen Behrens and Solis, {Luisa Maren}",

note = "Publisher Copyright: {\textcopyright} 2021, The Author(s).",

year = "2021",

month = jul,

doi = "10.1007/s00262-020-02820-4",

language = "English (US)",

volume = "70",

pages = "1965--1976",

journal = "Cancer Immunology, Immunotherapy",

issn = "0340-7004",

publisher = "Springer Science and Business Media Deutschland GmbH",

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TY - JOUR

T1 - CD73 expression defines immune, molecular, and clinicopathological subgroups of lung adenocarcinoma

AU - Rocha, Pedro

AU - Salazar, Ruth

AU - Zhang, Jiexin

AU - Ledesma, Debora

AU - Solorzano, Jose L.

AU - Mino, Barbara

AU - Villalobos, Pamela

AU - Dejima, Hitoshi

AU - Douse, Dzifa Y.

AU - Diao, Lixia

AU - Mitchell, Kyle Gregory

AU - Le, Xiuning

AU - Zhang, Jianjun

AU - Weissferdt, Annikka

AU - Parra-Cuentas, Edwin

AU - Cascone, Tina

AU - Rice, David C.

AU - Sepesi, Boris

AU - Kalhor, Neda

AU - Moran, Cesar

AU - Vaporciyan, Ara

AU - Heymach, John

AU - Gibbons, Don L.

AU - Lee, J. Jack

AU - Kadara, Humam

AU - Wistuba, Ignacio

AU - Behrens, Carmen

AU - Solis, Luisa Maren

PY - 2021/7

Y1 - 2021/7

N2 - Introduction: CD73 is a membrane-bound enzyme crucial in adenosine generation. The adenosinergic pathway plays a critical role in immunosuppression and in anti-tumor effects of immune checkpoint inhibitors (ICI). Here, we interrogated CD73 expression in a richly annotated cohort of human lung adenocarcinoma (LUAD) and its association with clinicopathological, immune, and molecular features to better understand the role of this immune marker in LUAD pathobiology. Materials and methods: Protein expression of CD73 was evaluated by immunohistochemistry in 106 archived LUADs from patients that underwent surgical treatment without neoadjuvant therapy. Total CD73 (T +) was calculated as the average of luminal (L +) and basolateral (BL +) percentage membrane expression scores for each LUAD and was used to classify tumors into three groups based on the extent of T CD73 expression (high, low, and negative). Results: CD73 expression was significantly and progressively increased across normal-appearing lung tissue, adenomatous atypical hyperplasia, adenocarcinoma in situ, minimally invasive adenocarcinoma, and LUAD. In LUAD, BL CD73 expression was associated with an increase in PD-L1 expression in tumor cells and increase of tumor-associated immune cells. Stratification of LUADs based on T CD73 extent also revealed that tumors with high expression of this enzyme overall exhibited significantly elevated immune infiltration and PD-L1 protein expression. Immune profiling demonstrated that T-cell inflammation and adenosine signatures were significantly higher in CD73-expressing lung adenocarcinomas relative to those lacking CD73. Conclusion: Our study suggests that higher CD73 expression is associated with an overall augmented host immune response, suggesting potential implications in the immune pathobiology of early stage lung adenocarcinoma. Our findings warrant further studies to explore the role of CD73 in immunotherapeutic response of LUAD.

AB - Introduction: CD73 is a membrane-bound enzyme crucial in adenosine generation. The adenosinergic pathway plays a critical role in immunosuppression and in anti-tumor effects of immune checkpoint inhibitors (ICI). Here, we interrogated CD73 expression in a richly annotated cohort of human lung adenocarcinoma (LUAD) and its association with clinicopathological, immune, and molecular features to better understand the role of this immune marker in LUAD pathobiology. Materials and methods: Protein expression of CD73 was evaluated by immunohistochemistry in 106 archived LUADs from patients that underwent surgical treatment without neoadjuvant therapy. Total CD73 (T +) was calculated as the average of luminal (L +) and basolateral (BL +) percentage membrane expression scores for each LUAD and was used to classify tumors into three groups based on the extent of T CD73 expression (high, low, and negative). Results: CD73 expression was significantly and progressively increased across normal-appearing lung tissue, adenomatous atypical hyperplasia, adenocarcinoma in situ, minimally invasive adenocarcinoma, and LUAD. In LUAD, BL CD73 expression was associated with an increase in PD-L1 expression in tumor cells and increase of tumor-associated immune cells. Stratification of LUADs based on T CD73 extent also revealed that tumors with high expression of this enzyme overall exhibited significantly elevated immune infiltration and PD-L1 protein expression. Immune profiling demonstrated that T-cell inflammation and adenosine signatures were significantly higher in CD73-expressing lung adenocarcinomas relative to those lacking CD73. Conclusion: Our study suggests that higher CD73 expression is associated with an overall augmented host immune response, suggesting potential implications in the immune pathobiology of early stage lung adenocarcinoma. Our findings warrant further studies to explore the role of CD73 in immunotherapeutic response of LUAD.

KW - Adenosinergic pathway

KW - CD73

KW - Immune profiling

KW - Lung adenocarcinoma

KW - PD-L1

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U2 - 10.1007/s00262-020-02820-4

DO - 10.1007/s00262-020-02820-4

M3 - Article

C2 - 33416944

AN - SCOPUS:85099100424

SN - 0340-7004

VL - 70

SP - 1965

EP - 1976

JO - Cancer Immunology, Immunotherapy

JF - Cancer Immunology, Immunotherapy

IS - 7

ER -

CD73 expression defines immune, molecular, and clinicopathological subgroups of lung adenocarcinoma

Abstract

Keywords

ASJC Scopus subject areas

MD Anderson CCSG core facilities

Access to Document

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