PTPN2 negatively regulates macrophage immune responses and cellular bioenergetics

PTPN2 is encoded by the protein tyrosine phosphatase N2 (also known as
TC-PTP) and is a negative regulator of cytokine signaling and macrophage
differentiation. In the past decade, our work and others', including
several pharmaceuticals, have emphasized that inhibition of PTPN2 and
PTPN1 (also known as PTP1B) may act as a new first-of-class cancer
immunotherapeutic. Although the potential roles of these two enzymes in
various immune cells have been broadly reported, the specific activity of
PTPN2 in regulating macrophage immune and metabolic responses has yet to
be fully elucidated. Hence, we sought to investigate the specific role of
PTPN2 in macrophage polarization and function. We used two different mouse
models to systematically and specifically inhibit the expression of PTPN2
in macrophages and utilized a chemical inhibitor with a macrophage human
cell line to assess their immune and metabolic profiles. We demonstrated
that PTPN2 ablation in macrophages alters their immunometabolic
transcriptome and enhances their pro-inflammatory response, as observed by
increased IFN-ɣ and nitric oxide production. PTPN2 deficiency also leads
to a dysregulation of mitochondrial respiration, as observed by decreased
oxygen consumption and ATP production. We establish herein that PTPN2
dampens the pro-inflammatory response of macrophages while altering their
mitochondrial respiration, validating its macrophage inhibition as a
contributing factor in the potency of systemic dual inhibition of PTPN1
and PTPN2 against cancer.