MHC Class I Loss in Triple-negative Breast Cancer

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.

Screening of Immune-Related Genes and Predicting the Immunotherapeutic Effects of Formononetin in Breast Cancer: A Bioinformatics Analysis

“…Currently, immunotherapy has been used to treat breast cancer via activating mechanisms of innate and adaptive immunities [57,58]. Immunosuppression is closely related to the development of malignant tumors [59], making immunotherapy a promising treatment option for breast cancer.…”

Epigenetic Regulation of Immunotherapy Response in Triple-Negative Breast Cancer

“…MHC class I impairment has been observed as a mechanism of immunotherapeutic resistance, particularly in the TNBC apocrine subtype [48] and metastatic TNBC [49]. In metastatic TNBC, high expression of the transmembrane protein MAL2 diminishes the level and stability of the antigen-loaded MHC class I on the cell membrane, promoting an ineffective antigen presentation and consequently limited recognition by CD8+ T-cells [50].…”

Breast cancer stem cell-derived tumors escape from γδ T cell immunosurveillance in vivo by modulating γδ T cell ligands

“…However, the efficacy of these treatments relies on the presence of tumor-specific antigens presented on MHC I molecules. The loss of MHC I expression and the concomitant lack of peptide presentation in cancer cells can undermine conventional αβ T cell recognition, and thus lead to tumor immune escape, which has been widely observed in cancers, including TNBC (Pedersen et al 2017; Dusenbery et al 2021; Dhatchinamoorthy et al 2021). To overcome this limitation, novel immunotherapies using unconventional non-MHC-restricted lymphocytes, such as γδ T cells are currently being investigated.…”