MHC Class I Loss in Triple-negative Breast Cancer: A Potential Barrier to PD-1/PD-L1 Checkpoint Inhibitors

• Published in: The American journal of surgical pathology Vol. 45; no. 5; p. 701
• Main Authors: Dusenbery, Anna C, Maniaci, Joseph L, Hillerson, Natalie D, Dill, Erik A, Bullock, Timothy N, Mills, Anne M
• Format: Journal Article
• Language: English
• Published: United States 01.05.2021
• Subjects: 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
• ISSN: 1532-0979
• DOI: 10.1097/PAS.0000000000001653

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.