Differential abundance of DNA damage sensors and innate immune signaling proteins in INPP4B negative TNBC classified by immunotype

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.