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

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posted on 2023-03-31, 19:22 authored by Jiqing Sai, Philip Owens, Sergey V. Novitskiy, Oriana E. Hawkins, Anna E. Vilgelm, Jinming Yang, Tammy Sobolik, Nicole Lavender, Andrew C. Johnson, Colt McClain, Gregory D. Ayers, Mark C. Kelley, Melinda Sanders, Ingrid A. Mayer, Harold L. Moses, Mark Boothby, Ann Richmond

<p>Supplementary Figure 1: BKM120 inhibited CD4+ T cell, not CD8+ T cell proliferation and had small effects on PyMT specific T cell mediated cytotoxicity only at a 1:50 E/T cell ratio. Supplementary Figure 2: Tumors were initiated as described in Figure 1 and BKM120 was delivered to PyMT-tumor bearing C57Bl/6 mice (n = 5) for different periods of time. Supplementary Figure 3C and 3D. Additional Flow Cytometry Analysis of Leukocyte populations in PD-1 treated animals. Supplementary Figure 3E and 3F. Myeloid FACS analysis and FoxP3 histology from BKM-120 and â�ºPD-1 treated PyMT Supplemental Figure 5: Implantation of expanded human T cells into NSG mice. Supplemental Figure 7: Effects of Loss of PI3KÎ³ on Leukocytes</p>

Funding

VA Senior Research Career Scientist Award

VICC Cancer Center Support Grant

NIH

VA CDA2

CTSA NIH

History

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DOI - Is supplement to PI3K Inhibition Reduces Mammary Tumor Growth and Facilitates Antitumor Immunity and Anti-PD1 Responses

ARTICLE 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 antitumor immunity.Experimental Design: The effect of PI3K inhibition on tumor growth, metastasis, and antitumor 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 (30 mg/kg, every day) or vehicle-treated mice and PI3Kγnull versus PI3KγWT mice. On the basis of the finding that PI3K inhibition resulted in a more inflammatory tumor leukocyte infiltrate, the therapeutic efficacy of BKM120 (30 mg/kg, every day) and anti-PD1 (100 μg, 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 antitumor 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 with either agent alone.Conclusions: PI3K inhibition slows tumor growth, enhances antitumor 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. Clin Cancer Res; 23(13); 3371–84. ©2016 AACR.