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

被引：98

作者：

Sai, Jiqing ^{[1
,2
]}

Owens, Philip ^{[1
,2
]}

Novitskiy, Sergey V. ^{[3
]}

Hawkins, Oriana E. ^{[1
,2
,7
]}

Vilgelm, Anna E. ^{[1
,2
]}

Yang, Jinming ^{[1
,2
]}

Sobolik, Tammy ^{[1
,2
]}

Lavender, Nicole ^{[1
,2
]}

Johnson, Andrew C. ^{[1
,2
]}

McClain, Colt ^{[4
,8
]}

Ayers, Gregory D. ^{[5
]}

Kelley, Mark C. ^{[6
]}

Sanders, Melinda ^{[4
]}

Mayer, Ingrid A. ^{[3
]}

Moses, Harold L. ^{[2
]}

Boothby, Mark ^{[4
]}

Richmond, Ann ^{[1
,2
]}

机构：

[1] Tennessee Valley Healthcare Syst, Dept Vet Affairs, Nashville, TN USA

[2] Vanderbilt Univ, Dept Canc Biol, 221 Kirkland Hall, Nashville, TN 37235 USA

[3] Vanderbilt Univ, Dept Med, Nashville, TN USA

[4] Vanderbilt Univ, Dept Pathol Microbiol & Immunol, 221 Kirkland Hall, Nashville, TN 37235 USA

[5] Vanderbilt Univ, Dept Biostat, 221 Kirkland Hall, Nashville, TN 37235 USA

[6] Vanderbilt Univ, Dept Surg Oncol, 221 Kirkland Hall, Nashville, TN 37235 USA

[7] ENTVantage DX, Ft Worth, TX USA

[8] St Thomas Hosp, Nashville, TN USA

来源：

CLINICAL CANCER RESEARCH | 2017年 / 23卷 / 13期

关键词：

NEGATIVE BREAST-CANCER; ORAL PAN-PI3K INHIBITOR; ADVANCED SOLID TUMORS; PIK3CA MUTATIONS; T-CELL; INFILTRATING LYMPHOCYTES; DOSE-ESCALATION; PTEN LOSS; IMMUNOTHERAPY; EXPRESSION;

D O I：

10.1158/1078-0432.CCR-16-2142

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

Purpose: Metastatic breast cancers continue to elude current therapeutic strategies, including those utilizing PI3K inhibitors. Given the prominent role of PI3K alpha,beta in tumor growth and PI3K gamma,delta 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 PI3K gamma-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 PI3K gamma(null) versus PI3K gamma(WT) 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 mg, 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 PI3K gamma in the host. The antitumor effect of PI3K gamma 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. (C) 2016 AACR.

引用

页码：3371 / 3384

页数：14