Pik3ip1 Is a Negative Immune Regulator that Inhibits Antitumor T-Cell Immunity

Abstract

Purpose: Multiple negative regulators restrict the ability of T cells to attack tumors. This work demonstrates the role of PI3Kinteracting protein 1 (Pik3ip1) in restraining T-cell responses and antitumor immunity. Experimental Design: An anti-Pik3ip1 mAb was generated to identify the Pik3ip1 expression pattern of hematopoietic cells. Pik3ip1 À/À mice and a Pik3ip1 fusion protein were generated to investigate the effect of Pik3ip1 on T-cellmediated antitumor immunity in MC38 and B16-F10 tumor models. Immunoblotting and confocal microscopy were used to identify inhibitory effects of Pik3ip1 on T-cell receptor (TCR) signaling. Pik3ip1 expression was quantified, and its impact on T-cell function in human tumors was measured. Results: We demonstrated that Pik3ip1 was predominantly expressed on T cells and served as an essential rheostat for T-cell-mediated immunity. A Pik3ip1 genetic deficiency led to enhanced T-cell responsiveness upon immunization with a neoantigen. Pik3ip1 À/À mice exhibited a marked increase in antitumor immunity and were resistant to tumor growth. Furthermore, Pik3ip1 extracellular domain fusion protein enhanced MC38 tumor growth was observed. Mechanistically, we found that Pik3ip1 inhibited TCR signaling by mediating the degradation of SLP76 through Pik3ip1 oligomerization via its extracellular region. Consistent with the results from the mouse models, PIK3IP1 expression correlated with T-cell dysfunction in human tumors. Conclusions: Our data reveal a critical role for Pik3ip1 as a novel inhibitory immune regulator of T-cell responses and provide a potential molecular target for cancer immunotherapy.

Control of T lymphocyte fate decisions by PI3K signaling

“…These results are consistent with our previous report that PIK3IP1 can restrain an inflammatory Th1 response 26 . The biological impact of this PI3K regulator has recently been expanded to include control of anti-tumor immunity 63 . This study employed mice with germline deficiency of PIK3IP1, which displayed significant resistance to the syngeneic transplantable tumors MC38 and B16F10 63 .…”

“…The biological impact of this PI3K regulator has recently been expanded to include control of anti-tumor immunity 63 . This study employed mice with germline deficiency of PIK3IP1, which displayed significant resistance to the syngeneic transplantable tumors MC38 and B16F10 63 . However, the cellular and molecular mechanisms underlying this enhanced tumor resistance are not fully understood.…”

“…As discussed above, the transmembrane protein PIK3IP1 represents a uniquely upstream regulator of the PI3K pathway whose impact on the effector/memory axis has yet to be fully understood. Despite the still-incomplete mechanistic understanding of PIK3IP1, its utility as a potential target for cancer immunotherapy has already shown promise 63 .…”

Human Endogenous Retrovirus Expression Is Upregulated in the Breast Cancer Microenvironment of HIV Infected Women: A Pilot Study

“…In addition, by analyzing immune T-cell signature genes, we showed PIK3IP1 upregulated in HIV-positive breast cancer samples. The PIK3P1 protein is a negative regulator of T-cell activation and of antitumor T-cell immunity (83,84). Interestingly, tumor-infiltrating lymphocytes are able to induce an immune response, and their presence is often associated with a good prognosis across a spectrum of malignancies in HIV-negative patients (85,86).…”

827 Elucidating the roles of PIK3IP1/TrIP immune regulation on distinct T cell subsets in the context of cancer

“…1 This negative immune regulation was just recently reported to promote antitumor immunity, implicating TrIP as a potential immunotherapy target. 2 Interestingly, although all effector subsets reexpress TrIP to varying degrees, public expression data shows that Treg cells maintain higher TrIP message than other Teffector subsets. 3 Methods Using a conditional TrIP knockout mouse model developed in our lab, we have begun to interrogate how TrIP expression regulates the opposing activities of CD8+ T cells vs. Treg and how these affect the overall tumor immune landscape.…”