Expression of the MHC Class II Pathway in Triple-Negative Breast Cancer Tumor Cells Is Associated with a Good Prognosis and Infiltrating Lymphocytes

Abstract

Triple negative breast cancer (TNBC) is a subtype with heterogeneous patient outcomes. Approximately forty percent of patients experience rapid relapse, while the remaining patients have long-term disease-free survival. To determine if there are molecular differences between primary tumors that predict prognosis we performed RNA-seq on 47 macro-dissected tumors from newly diagnosed patients with TNBC (n = 47; 22 relapse, 25 no relapse; follow-up median 8 years, range 2–11 years). We discovered that expression of the MHC class II (MHC II) antigen presentation pathway in tumor tissue was the most significant pathway associated with progression-free survival (hazard ratio (HR) = 0.36, log-rank P = 0.0098). The association between MHC II pathway expression and good prognosis was confirmed in a public gene expression database of 199 TNBC cases (HR = 0.28, log-rank P = 4.5 × 10−8). Further analysis of immunohistochemistry, laser-capture micro-dissected tumors, and TNBC cell lines demonstrated that tumor cells, in addition to immune cells, aberrantly express the MHC II pathway. MHC II pathway expression was also associated with B cell and T cell infiltration in the tumor. Together these data support the model that aberrant expression of the MHC II pathway in TNBC tumor cells may trigger an antitumor immune response that reduces the rate of relapse and enhances progression-free survival.

Morphology and tumour‐infiltrating lymphocytes in high‐stage, high‐grade serous ovarian carcinoma correlated with long‐term survival

“…Surprisingly, in our long‐term survivor group there were as many cases with reduced or even totally negative MHC1 expression as in controls, showing that in the tumours with excellent outcome immune escape also occurs. Less is known about MHC2 expression in cancer cells; interestingly, however, in long‐term survivors a higher positivity rate than in controls was seen. A recent study described 96 advanced‐stage HGSC with exceptional survival .…”

The antitumor effects of entinostat in ovarian cancer require adaptive immunity

“…Furthermore, these findings have been supported in clinical studies of patients with breast and ovarian cancer. In both disease sites, increased tumor cell MHCII expression strongly correlates with higher numbers of infiltrating cytotoxic T cells, which in turn is associated with improved survival [18, 19, 39]. …”

Epigenetic therapy for the treatment of epithelial ovarian cancer: A clinical review

“…In diffuse large B-cell lymphoma, treatment with HDAC inhibitors has resulted in upregulation of the MHCII pathway, which is known to be associated with improved survival in both breast and ovarian carcinoma (Cycon et al, 2013, Forero et al, 2016). In our experience, treatment with the HDAC inhibitor entinostat has resulted in increased MHCII expression in vitro in human and murine ovarian cancer cell lines, as well as in vivo in both a patient-derived xenograft and a syngeneic mouse model (unpublished data).…”

“…In diffuse large B cell lymphoma, HDAC inhibitors have been shown to upregulate major histocompatibility complex class II (MHCII) expression on tumor cells via the transcriptional regulator CIITA (Cycon et al, 2013), and increased MHCII expression has been associated with improved immunogenicity and tumor rejection in animal models of breast, prostate, and renal cell carcinoma (Hillman et al, 2004, Mortara et al, 2006). Additionally, MHCII expression has been associated with increased infiltration of CD8 lymphocytes and improved survival in patients with triple negative breast cancer and papillary serous ovarian cancer (Cycon et al, 2013, Forero et al, 2016). …”