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Differential Abundance of DNA Damage Sensors and Innate Immune Signaling Proteins in Inositol Polyphosphate
F Scott Heinemann1, Paul D Gershon2
1Department of Pathology, Hoag Memorial Hospital Presbyterian, Newport Beach, California.
Abstract:
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.
Insights
Triple-negative breast cancer (TNBC) subtypes show distinct protein profiles in neoplastic cells. T-cell infiltrated TNBC overexpresses proteins involved in immune signaling and DNA damage response, unlike T-cell desert TNBC.
Area of Science:
- Oncology
- Immunology
- Proteomics
Background:
- The tumor microenvironment's influence on neoplastic cells in triple-negative breast cancer (TNBC) is not fully understood.
- TNBC exhibits diverse immunotypes, including T-cell desert and T-cell infiltrated (TCI) subtypes.
Purpose of the Study:
- To compare protein expression in neoplastic cells between T-cell desert and TCI TNBC immunotypes.
- To identify proteins correlating with T-cell infiltration levels in TNBC.
Main Methods:
- Label-free quantitative protein mass spectrometry on formalin-fixed, paraffin-embedded TNBC tissue sections.
- Comparative proteomic analysis of 439 significantly differentially abundant proteins between TCI and T-cell desert TNBC.
- Immunohistochemical validation of key differentially abundant proteins in a larger cohort of TNBC samples.
Main Results:
- 361 proteins were significantly overabundant in TCI-TNBC compared to T-cell desert TNBC.
- Overabundant proteins in TCI-TNBC are associated with MHC-I antigen processing, viral defense, DNA damage response, and innate immune signaling.
- Elevated levels of interferon-γ-inducible protein 16, apoptosis-associated speck-like protein containing a CARD (ASC), and gasdermin D were observed in TCI-TNBC neoplastic cells.
- Barrier to autointegration factor (BAF) was elevated in T-cell desert TNBC neoplastic cells.
Conclusions:
- A novel correlation exists between T-cell infiltration levels in TNBC and the abundance of specific proteins within neoplastic cells.
- These proteins modulate innate immune signaling pathways in response to DNA damage, offering potential therapeutic targets.
