Differential Abundance of DNA Damage Sensors and Innate Immune Signaling Proteins in Inositol Polyphosphate 4-Phosphatase Type II-Negative Triple-Negative Breast Cancer Classified by Immunotype.

Autor:	Heinemann FS; Department of Pathology, Hoag Memorial Hospital Presbyterian, Newport Beach, California. Electronic address: fsheinemann@hoaghospital.org., Gershon PD; Department of Molecular Biology and Biochemistry, University of California, Irvine, California. Electronic address: pgershon@uci.edu.
Jazyk:	angličtina
Zdroj:	The American journal of pathology [Am J Pathol] 2024 Nov; Vol. 194 (11), pp. 2212-2232. Date of Electronic Publication: 2024 Aug 13.
DOI:	10.1016/j.ajpath.2024.07.015
Abstrakt:	The influence of neoplastic cells on the tumor microenvironment is poorly understood. In this study, eight patient samples representing two immunotypes of triple-negative breast cancer (TNBC), defined by quantitative histologic criteria as T-cell desert and T-cell infiltrated (TCI), were compared via label-free quantitative protein mass spectrometry of material extracted directly from targeted regions of formalin-fixed, paraffin-embedded tissue sections. Of 2934 proteins quantitated, 439 were significantly differentially abundant, among which 361 were overabundant in TCI-TNBC. The 361-protein group included proteins involved in major histocompatibility complex-I antigen processing and presentation, viral defense, DNA damage response, and innate immune signaling. Immunohistochemical validation of selected proteins showed good positive correlation between neoplastic cell histoscores and label-free quantitation. Extension of immunohistochemical analysis to a total of 58 inositol polyphosphate 4-phosphatase type II-negative TNBC confirmed elevated levels of the DNA damage sensor interferon-γ-inducible protein 16, inflammasome adaptor apoptosis-associated speck-like protein containing a CARD (ASC), and pore-forming protein gasdermin D in TCI-TNBC neoplastic cells. By contrast, cGMP-AMP synthase inhibitor barrier to autointegration factor (BAF) was elevated in the neoplastic cells of T-cell desert TNBC. These findings demonstrate a previously unknown correlation between the degree of T-cell infiltration in inositol polyphosphate 4-phosphatase type II-negative TNBC and the levels, in cognate neoplastic cells, of proteins that modulate innate immune signaling in response to DNA damage. Competing Interests: Disclosure Statement None declared. (Copyright © 2024 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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