PI3K Inhibition Reduces Mammary Tumor Growth and Facilitates Antitumor Immunity and Anti-PD1 Responses

Abstract

Purpose Metastatic breast cancers continue to elude current therapeutic strategies, including those utilizing PI3K inhibitors. Given the prominent role of PI3Kα,β in tumor growth and PI3Kγ,δ in immune cell function, we sought to determine whether PI3K inhibition altered anti-tumor immunity. Experimental Design The effect of PI3K inhibition on tumor growth, metastasis, and anti-tumor immune response was characterized in mouse models utilizing orthotopic implants of 4T1 or PyMT mammary tumors into syngeneic or PI3Kγ null mice, and patient-derived breast cancer xenografts in humanized mice. Tumor infiltrating leukocytes were characterized by IHC and FACS analysis in BKM120 (30mg/kg, QD) or vehicle treated mice and PI3Kγnull versus PI3KγWT mice. Based on the finding that PI3K inhibition resulted in a more inflammatory tumor leukocyte infiltrate, the therapeutic efficacy of BKM120 (30mg/kg, QD) and anti-PD1 (100µg, twice weekly) was evaluated in PyMT tumor bearing mice. Results Our findings show that PI3K activity facilitates tumor growth and surprisingly, restrains tumor immune surveillance. These activities could be partially suppressed by BKM120 or by genetic deletion of PI3Kγ in the host. The anti-tumor effect of PI3Kγ loss in host, but not tumor, was partially reversed by CD8+T cell depletion. Treatment with therapeutic doses of both BKM120 and antibody to PD-1 resulted in consistent inhibition of tumor growth compared to either agent alone. Conclusions PI3K inhibition slows tumor growth, enhances anti-tumor immunity, and heightens susceptibility to immune checkpoint inhibitors. We propose that combining PI3K inhibition with anti-PD1 may be a viable therapeutic approach for triple negative breast cancer.

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

“…During T-cell activation, Src homology 2 domain-containing leukocyte protein of 76 kDa (SLP76) associates with PI3K subunit p85, leading to the downstream Akt activation (8). Inhibition of PI3K isoform promoted robust CD8 þ T-cell activation, improved antitumor immunity, and host survival by enhancing the cytokines production of cytotoxic lymphocytes (9,10). PI3K/Akt/mTOR complex has also been shown to be involved in the differentiation of various immunosuppressive T-cell subsets including Foxp3 þ Treg cell and tumor-associated macrophages (11,12).…”

Multi-Omics Profiling Reveals Distinct Microenvironment Characterization and Suggests Immune Escape Mechanisms of Triple-Negative Breast Cancer

“…Therefore, we speculated that hyper-activated PI3K-AKT pathway in tumor cells might play a major role in suppressing immune infiltration in cluster 2, such as through TGF-b secretion and CAF differentiation. In particular, previous studies have revealed that pan-PI3K inhibition enhances antitumor immunity and anti-PD1 response in breast cancer (45).…”

Targeting monoamine oxidase A-regulated TAM polarization for cancer immunotherapy

“…Many of these TAM reprogramming strategies are currently under active clinical evaluation 39 . Notably, CD40 agonists work through activating CD40L-downstream NF-kB pathway 87,89 ; HDAC inhibitors work through altering histone modi cations 86,90,91 ; PI3Kγ inhibitors work through stimulating NF-κB activation while inhibiting C/EBPβ activation 88,92,93 ; and creatine uptake works through regulating cytokine responses 40 . Our discovery of MAO-A as a critical regulator of TAM polarization through modulating oxidative stress provides a new drug target and a new mechanism of action (MOA) for expanding TAM-repolarizing strategies.…”