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107 Tumor specific MHC-I expression determines the local immune microenvironment in breast cancer
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  1. Xiaopeng Sun,
  2. Brandie Taylor,
  3. Paula Gonzalez Ericsson,
  4. Violeta Sanchez and
  5. Justin Balko
  1. Vanderbilt University Medical Center, Nashville, TN, USA

Abstract

Background Tumors employ various immune escape mechanisms, including downregulation of major histocompatibility complex I (MHC-I) expression, to avoid T cell-mediated anti-tumor immunity. Although complete MHC-I loss is possible, most tumors express MHC-I in a heterogeneous manner, with a mix of MHC-I high, mid, and low expressing tumor cells. However, the intratumor MHC-I heterogeneity and its impact on the immune microenvironment still require further study. The goal of this study is to investigate MHC-I expressional heterogeneity in breast cancer and characterize the immune landscape, with a focus on CD8 T cells, which target MHC-I expressing tumor cells, and NK cells, which target MHC-I negative/low tumor cells, in a spatial manner within the tumor microenvironment.

Methods We performed quantitative immunofluorescence for MHC-I, CD8, CD56 (NK cell marker), and pan-cytokeratin on breast cancer tumors (n=314) from diverse subtypes to obtain single-cell resolution MHC-I expression and spatial information of tumor and immune cells. Ripley’s K function was used to analyze the spatial distribution of MHC-I high, mid, and low expressing tumor cells. We also performed density-based clustering to arrange neighboring tumor cells into clusters and subsequently examine the local immune cell infiltration.

Results All clinical breast cancer subtypes showed high variability in MHC-I expression, with triple-negative breast cancer (TNBC) having the highest MHC-I expression and the largest percentage of tumors with multimodal MHC-I expression (consisting of MHC-I high, mid, and low expressing tumor cells). Both MHC-I high and low expressing tumor cells, especially those in TNBC, tend to cluster and create tumoral MHC-I hot and cold spots. Meanwhile, the MHC-I high-expressing stromal cells and CD8 T cells clustered with tumoral MHC-I hot spots, while MHC-I cold spots exhibited the lowest lymphocyte infiltration and clustered with MHC-I low-expressing stromal cells. Interestingly, heterogenous MHC-I tumor clusters (those with mixed high and low expressing cells) had the highest levels of infiltrating NK cells.

Conclusions Our work reveals the heterogeneity of MHC-I expression among different breast cancer subtypes. TNBC, the immune checkpoint inhibitor (ICI)-sensitive subtype, is characterized by the highest MHC-I expression and well-defined MHC-I hot and cold spots. Additionally, the local immune landscape around MHC-I hot, cold, and heterogeneous clusters are significantly different. Increased NK cell infiltration in areas where tumor cells heterogeneously express MHC-I was also consistent with our preclinical heterogeneous MHC-I mammary tumor model. Those results suggested that immunotherapy-resistant, MHC-I heterogeneous tumors may be sensitized by combining an NK cell activation drug, such as anti-NKG2A, with already-available ICIs.

Ethics Approval Samples involved in this study are under IRB030747 and INEN 10–018

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