MHC Class I Loss in Triple-negative Breast Cancer: A Potential Barrier to PD-1/PD-L1 Checkpoint Inhibitors. (May 2021)

• Record Type: Journal Article
• Authors: Dusenbery, Anna C.; Maniaci, Joseph L.; Hillerson, Natalie D.; Dill, Erik A.; Bullock, Timothy N.; Mills, Anne M.
• Is Part Of: American journal of surgical pathology. Volume 45:Number 5(2021)
• Publication Date: 2021-05
• Subjects: MHC class I -- PD-L1 -- triple-negative breast cancer; Pathology, Surgical -- Periodicals; 617.0705
• DOI: 10.1097/PAS.0000000000001653
• Languages: English
• ISSNs: 0147-5185

Abstract

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. Abstract : Supplemental Digital Content is available in the text.