Original ArticlesMHC Class I Loss in Triple-negative Breast Cancer A Potential Barrier to PD-1/PD-L1 Checkpoint InhibitorsDusenbery, Anna C. MD*; Maniaci, Joseph L. BS†; Hillerson, Natalie D. BS†; Dill, Erik A. MD*; Bullock, Timothy N. PhD*; Mills, Anne M. MD*Author Information *University of Virginia Department of Pathology †University of Virginia School of Medicine, Charlottesville, VA Conflicts of Interest and Source of Funding: The authors have disclosed that they have no significant relationships with, or financial interest in, any commercial companies pertaining to this article. Correspondence: Anne M. Mills, MD, University of Virginia Department of Pathology, 1215 Lee Street HEP 3rd Floor, Charlottesville, VA 22908 (e-mail: [email protected]). The American Journal of Surgical Pathology: May 2021 - Volume 45 - Issue 5 - p 701-707 doi: 10.1097/PAS.0000000000001653 Buy SDC Metrics 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. Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.