Ferritin Heavy Chain in Triple Negative Breast Cancer: A Favorable Prognostic Marker that Relates to a Cluster of Differentiation 8 Positive (CD8+) Effector T-cell Response

Abstract

Ferritin heavy chain (FTH1) is a 21-kDa subunit of the ferritin complex, known for its role in iron metabolism, and which has recently been identified as a favorable prognostic protein for triple negative breast cancer (TNBC) patients. Currently, it is not well understood how FTH1 contributes to an anti-tumor response. Here, we explored whether expression and cellular compartmentalization of FTH1 correlates to an effective immune response in TNBC patients. Analysis of the tumor tissue transcriptome, complemented with in silico pathway analysis, revealed that FTH1 was an integral part of an immunomodulatory network of cytokine signaling, adaptive immunity, and cell death. These findings were confirmed using mass spectrometry (MS)-derived proteomic data, and immunohistochemical staining of tissue microarrays. We observed that FTH1 is localized in both the cytoplasm and/or nucleus of cancer cells. However, high cytoplasmic (c) FTH1 was associated with favorable prognosis (Log-rank p = 0.001), whereas nuclear (n) FTH1 staining was associated with adverse prognosis (Log-rank p = 0.019). cFTH1 staining significantly correlated with total FTH1 expression in TNBC tissue samples, as measured by MS analysis (Rs = 0.473, p = 0.0007), but nFTH1 staining did not (Rs = 0.197, p = 0.1801). Notably, IFN γ-producing CD8+ effector T cells, but not CD4+ T cells, were preferentially enriched in tumors with high expression of cFTH1 (p = 0.02). Collectively, our data provide evidence toward new immune regulatory properties of FTH1 in TNBC, which may facilitate development of novel therapeutic targets.

Prognostic significance of nuclear expression of UMP-CMP kinase in triple negative breast cancer patients

“…FTH1) belonging to the same signature314. While the cytoplasmic component appeared to be ubiquitous and homogeneous, as staining intensity was generally weak or moderate and present in the majority (>70%) of tumor cells, nCMPK1 displayed a higher degree of heterogeneity in terms of expression and number of stained tumor cells.…”

Elucidating immunologic mechanisms of PROSTVAC cancer immunotherapy

“…Less is known about the relative contributions of these T cell subsets to productive immunity against cancer, but it is feasible to assume that polyfunctional CD8 T cells will prove to be more efficient in cancer immunotherapy. Higher percentages of CD8 T cells in the tumor have been correlated with better prognosis for a variety of cancers [ 26 , 27 ].…”

Advancement of mass spectrometry-based proteomics technologies to explore triple negative breast cancer

“…Liu et al showed that over 60% of the TNBC patients who received adjuvant chemotherapy using the conventional St. Gallen 95 and NIH 96 criteria were unnecessarily treated based on the 11-proteins signature defined in this study. A subsequent proteomics study 97 further validated that FTH1, an immunomodulatory molecule involved in augmentation of CD8+ T cells in the tumour area, is a potential therapeutic target in TNBC.…”