MHC Class I Loss in Triple-negative Breast Cancer: A Potential Barrier to PD-1/PD-L1 Checkpoint Inhibitors
Suppression of the immune system is intimately linked to the development and progression of malignancy, and immune modulating treatment options have shown promise in a variety of tumor types, including some triple-negative breast cancers (TNBC). The most dramatic therapeutic success has been seen wi...
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Published in | The American journal of surgical pathology Vol. 45; no. 5; p. 701 |
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Main Authors | , , , , , |
Format | Journal Article |
Language | English |
Published |
United States
01.05.2021
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Subjects | |
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Abstract | Suppression of the immune system is intimately linked to the development and progression of malignancy, and immune modulating treatment options have shown promise in a variety of tumor types, including some triple-negative breast cancers (TNBC). The most dramatic therapeutic success has been seen with immune checkpoint inhibitors targeting programmed cell death protein 1 (PD-1) and its ligand, PD-L1. Difficulty remains, however, in appropriate patient selection for treatment, as many PD-L1-positive cancers fail to show durable responses to PD-1/PD-L1 inhibition. Checkpoint inhibitor targeting of the adaptive immune response relies on the presence of major histocompatibility complex (MHC) class I molecules on the tumor cell surface for tumor antigen presentation. MHC class I loss has been previously described in breast cancer and represents a putative mechanism of immunotherapeutic resistance in this tumor type. One hundred seventeen invasive primary breast carcinomas with a range of histologic subtypes were evaluated on tissue microarrays containing formalin-fixed paraffin-embedded tissue. Loss of MHC class I expression was common among breast cancers, with greater than half of cases demonstrating either subclonal or diffuse loss. Fifty-nine percent of TNBC demonstrated loss of MHC class I, including 46% of those meeting the Food and Drug Administration-approved threshold of 1% for tumor-associated immune cell PD-L1 expression. MHC class I loss was particularly common in the apocrine subtype of TNBC (78%). MHC class I's employment as a predictive biomarker should be considered, as its loss may represent a barrier to successful enhancement of the antitumor adaptive immune response by PD-1/PD-L1 inhibition. |
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AbstractList | Suppression of the immune system is intimately linked to the development and progression of malignancy, and immune modulating treatment options have shown promise in a variety of tumor types, including some triple-negative breast cancers (TNBC). The most dramatic therapeutic success has been seen with immune checkpoint inhibitors targeting programmed cell death protein 1 (PD-1) and its ligand, PD-L1. Difficulty remains, however, in appropriate patient selection for treatment, as many PD-L1-positive cancers fail to show durable responses to PD-1/PD-L1 inhibition. Checkpoint inhibitor targeting of the adaptive immune response relies on the presence of major histocompatibility complex (MHC) class I molecules on the tumor cell surface for tumor antigen presentation. MHC class I loss has been previously described in breast cancer and represents a putative mechanism of immunotherapeutic resistance in this tumor type. One hundred seventeen invasive primary breast carcinomas with a range of histologic subtypes were evaluated on tissue microarrays containing formalin-fixed paraffin-embedded tissue. Loss of MHC class I expression was common among breast cancers, with greater than half of cases demonstrating either subclonal or diffuse loss. Fifty-nine percent of TNBC demonstrated loss of MHC class I, including 46% of those meeting the Food and Drug Administration-approved threshold of 1% for tumor-associated immune cell PD-L1 expression. MHC class I loss was particularly common in the apocrine subtype of TNBC (78%). MHC class I's employment as a predictive biomarker should be considered, as its loss may represent a barrier to successful enhancement of the antitumor adaptive immune response by PD-1/PD-L1 inhibition. |
Author | Dill, Erik A Dusenbery, Anna C Bullock, Timothy N Hillerson, Natalie D Maniaci, Joseph L Mills, Anne M |
Author_xml | – sequence: 1 givenname: Anna C surname: Dusenbery fullname: Dusenbery, Anna C organization: University of Virginia Department of Pathology – sequence: 2 givenname: Joseph L surname: Maniaci fullname: Maniaci, Joseph L organization: University of Virginia School of Medicine, Charlottesville, VA – sequence: 3 givenname: Natalie D surname: Hillerson fullname: Hillerson, Natalie D organization: University of Virginia School of Medicine, Charlottesville, VA – sequence: 4 givenname: Erik A surname: Dill fullname: Dill, Erik A organization: University of Virginia Department of Pathology – sequence: 5 givenname: Timothy N surname: Bullock fullname: Bullock, Timothy N organization: University of Virginia Department of Pathology – sequence: 6 givenname: Anne M surname: Mills fullname: Mills, Anne M organization: University of Virginia Department of Pathology |
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SubjectTerms | Adaptive Immunity Adult Aged Aged, 80 and over B7-H1 Antigen - analysis B7-H1 Antigen - antagonists & inhibitors Biomarkers, Tumor - analysis Biomarkers, Tumor - antagonists & inhibitors Female Histocompatibility Antigens Class I - analysis Humans Immune Checkpoint Inhibitors - therapeutic use Immunohistochemistry Middle Aged Patient Selection Programmed Cell Death 1 Receptor - analysis Programmed Cell Death 1 Receptor - antagonists & inhibitors Tissue Array Analysis Triple Negative Breast Neoplasms - drug therapy Triple Negative Breast Neoplasms - immunology Triple Negative Breast Neoplasms - pathology Tumor Microenvironment |
Title | MHC Class I Loss in Triple-negative Breast Cancer: A Potential Barrier to PD-1/PD-L1 Checkpoint Inhibitors |
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