New onset lymphopenia in patients with relapsing multiple sclerosis switching from long-standing dimethyl fumarate treatment to diroximel fumarate: A case series.

Lymphopenia is a known adverse effect in patients with relapsing multiple sclerosis (RMS) treated with fumaric acids. We present a case series of four patients diagnosed with RMS with prolonged lymphocyte stability on dimethyl fumarate for over 1 year who developed significant lymphopenia after transitioning to diroximel fumarate. This case series highlights the need for further research to elucidate the risk of lymphopenia in patients switching between fumaric acids.

The Meharry-Vanderbilt-Tennessee State University Cancer Partnership (MVTCP): History and Highlights of 20 Years of Accomplishments.

Cancer health disparities among populations are the result of a combination of socioeconomic, environmental, behavioral, and biological factors, which affect cancer incidence, prevalence, mortality, survivorship, financial burden, and screening rates. The long-standing Meharry Medical College (MMC), Vanderbilt-Ingram Cancer Center (VICC), Tennessee State University (TSU) Cancer Partnership has built an exceptional cancer research and training environment to support the efforts of diverse investigators in addressing disparities. Over the past 20 years, collaborative partnership efforts across multiple disciplines have supported research into the determinants of cancer health disparities at a National Cancer Institute-designated comprehensive cancer center (VICC) along with enhancing research infrastructure and training at MMC and TSU, two institutions that serve predominantly underserved populations and underrepresented students. Moreover, the geographical placement of this partnership in Tennessee, a region with some of the highest cancer incidence and mortality in the United States, has provided an especially important opportunity to positively affect outcomes for cancer patients.

Blocking VCAM-1 inhibits pancreatic tumour progression and cancer-associated thrombosis/thromboembolism.

OBJECTIVE: Pancreatic ductal adenocarcinoma (PDAC) is the deadliest cancer. Cancer-associated thrombosis/thromboembolism (CAT), frequently observed in PDAC, is known as a poor prognostic factor. Here, we investigated the underlying mechanisms between PDAC and CAT, and performed a trial of therapeutic approach for PDAC using a genetically engineered mouse model, PKF (Ptf1acre/+;LSL-KrasG12D/+;Tgfbr2flox/flox ). DESIGN: Presence of CAT in PKF mice was detected by systemic autopsy. Plasma cytokines were screened by cytokine antibody array. Murine and human plasma atrial natriuretic peptide (ANP) and soluble vascular cell adhesion molecule 1 (sVCAM-1) were determined by ELISA. Distribution of VCAM-1 in PKF mice and human autopsy samples was detected by immunohistochemistry. PKF mice were treated with anti-VCAM-1 antibody and the effects on survival, distribution of CAT and the tumour histology were analysed. RESULTS: We found spontaneous CAT with cardiomegaly in 68.4% PKF mice. Increase of plasma ANP and sVCAM-1 was observed in PKF mice and PDAC patients with CAT. VCAM-1 was detected in the activated endothelium and thrombi. Administration of anti-VCAM-1 antibody to PKF mice inhibited tumour growth, neutrophil/macrophage infiltration, tumour angiogenesis and progression of CAT; moreover, it dramatically extended survival (from 61 to 253 days, p<0.01). CONCLUSION: Blocking VCAM-1/sVCAM-1 might be a potent therapeutic approach for PDAC as well as CAT, which can contribute to the prognosis. Increase of plasma ANP and sVCAM-1 might be a diagnostic approach for CAT in PDAC.

Soluble VCAM-1 promotes gemcitabine resistance via macrophage infiltration and predicts therapeutic response in pancreatic cancer.

Pancreatic cancer is one of the malignant diseases with the worst prognosis. Resistance to chemotherapy is a major difficulty in treating the disease. We analyzed plasma samples from a genetically engineered mouse model of pancreatic cancer and found soluble vascular cell adhesion molecule-1 (sVCAM-1) increases in response to gemcitabine treatment. VCAM-1 was expressed and secreted by murine and human pancreatic cancer cells. Subcutaneous allograft tumors with overexpression or knock-down of VCAM-1, as well as VCAM-1-blocking treatment in the spontaneous mouse model of pancreatic cancer, revealed that sVCAM-1 promotes tumor growth and resistance to gemcitabine treatment in vivo but not in vitro. By analyzing allograft tumors and co-culture experiments, we found macrophages were attracted by sVCAM-1 to the tumor microenvironment and facilitated resistance to gemcitabine in tumor cells. In a clinical setting, we found that the change of sVCAM-1 in the plasma of patients with advanced pancreatic cancer was an independent prognostic factor for gemcitabine treatment. Collectively, gemcitabine treatment increases the release of sVCAM-1 from pancreatic cancer cells, which attracts macrophages into the tumor, thereby promoting the resistance to gemcitabine treatment. sVCAM-1 may be a potent clinical biomarker and a potential target for the therapy in pancreatic cancer.

Inhibition of transforming growth factor-ß signaling in myeloid cells ameliorates aortic aneurysmal formation in Marfan syndrome.

Increased transforming growth factor-ß (TGF-ß) signaling contributes to the pathophysiology of aortic aneurysm in Marfan syndrome (MFS). Recent reports indicate that a small but significant number of inflammatory cells are infiltrated into the aortic media and adventitia in MFS. However, little is known about the contribution of myeloid cells to aortic aneurysmal formation. In this study, we ablated the TGF-ß type II receptor gene Tgfbr2 in myeloid cells of Fbn1C1039G/+ MFS mice (Fbn1C1039G/+;LysM-Cre/+;Tgfbr2fl/fl mice, hereinafter called Fbn1C1039G/+;Tgfbr2MyeKO) and evaluated macrophage infiltration and TGF-ß signaling in the aorta. Aneurysmal formation with fragmentation and disarray of medial elastic fibers observed in MFS mice was significantly ameliorated in Fbn1C1039G/+;Tgfbr2MyeKO mice. In the aorta of Fbn1C1039G/+;Tgfbr2MyeKO mice, both canonical and noncanonical TGF-ß signals were attenuated and the number of infiltrated F4/80-positive macrophages was significantly reduced. In vitro, TGF-ß enhanced the migration capacity of RAW264.7 macrophages. These findings suggest that TGF-ß signaling in myeloid cells promotes aortic aneurysmal formation and its inhibition might be a novel therapeutic target in MFS.

Myeloid Cell-Derived TGFß Signaling Regulates ECM Deposition in Mammary Carcinoma via Adenosine-Dependent Mechanisms.

TGFß plays a crucial role in the tumor microenvironment by regulating cell-cell and cell-stroma interactions. We previously demonstrated that TGFß signaling on myeloid cells regulates expression of CD73, a key enzyme for production of adenosine, a protumorigenic metabolite implicated in regulation of tumor cell behaviors, immune response, and angiogenesis. Here, using an MMTV-PyMT mouse mammary tumor model, we discovered that deletion of TGFß signaling on myeloid cells (PyMT/TGFßRIILysM) affects extracellular matrix (ECM) formation in tumor tissue, specifically increasing collagen and decreasing fibronectin deposition. These changes were associated with mitigated tumor growth and reduced metastases. Reduced TGFß signaling on fibroblasts was associated with their proximity to CD73+ myeloid cells in tumor tissue. Consistent with these findings, adenosine significantly downregulated TGFß signaling on fibroblasts, an effect regulated by A2A and A2B adenosine receptors. METABRIC dataset analysis revealed that patients with triple-negative breast cancer and basal type harbored a similar signature of adenosine and ECM profiles; high expression of A2B adenosine receptors correlated with decreased expression of Col1 and was associated with poor outcome. Taken together, our studies reveal a new role for TGFß signaling on myeloid cells in tumorigenesis. This discovered cross-talk between TGFß/CD73 on myeloid cells and TGFß signaling on fibroblasts can contribute to ECM remodeling and protumorigenic actions of cancer-associated fibroblasts. SIGNIFICANCE: TGFß signaling on fibroblasts is decreased in breast cancer, correlates with poor prognosis, and appears to be driven by adenosine that accelerates tumor progression and metastasis via ECM remodeling.

Challenges and Opportunities to Updating Prescribing Information for Longstanding Oncology Drugs.

A number of important drugs used to treat cancer-many of which serve as the backbone of modern chemotherapy regimens-have outdated prescribing information in their drug labeling. The Food and Drug Administration is undertaking a pilot project to develop a process and criteria for updating prescribing information for longstanding oncology drugs, based on the breadth of knowledge the cancer community has accumulated with the use of these drugs over time. This article highlights a number of considerations for labeling updates, including selecting priorities for updating; data sources and evidentiary criteria; as well as the risks, challenges, and opportunities for iterative review to ensure prescribing information for oncology drugs remains relevant to current clinical practice.

Blocking CXCLs-CXCR2 axis in tumor-stromal interactions contributes to survival in a mouse model of pancreatic ductal adenocarcinoma through reduced cell invasion/migration and a shift of immune-inflammatory microenvironment.

Pancreatic ductal adenocarcinoma (PDAC) is characterized by dense stromal reaction (desmoplasia). We have previously reported that mice with conditional KrasG12D mutation and knockout of TGF-ß receptor type II (Tgfbr2), PKF mice, develop PDAC with desmoplasia modulated by CXC chemokines that are produced by PDAC cells through tumor-stromal interaction. In this study, we further discovered that PDAC and cancer-associated fibroblast (CAF) accelerated each other's invasion and migration through the CXC chemokines-receptor (CXCLs-CXCR2) axis. Heterozygous knockout of Cxcr2 in PKF mice (PKF2h mice) prolonged survival and inhibited both tumor angiogenesis and PDAC microinvasion. Infiltration of neutrophils, myeloid-derived suppressor cells (MDSCs), and arginase-1+ M2-like tumor-associated macrophages (TAMs) significantly decreased in the tumors of PKF2h mice, whereas inducible nitric oxide synthase (iNOS)+ M1-like TAMs and apoptotic tumor cells markedly increased, which indicated that blockade of the CXCLs-CXCR2 axis resulted in a shift of immune-inflammatory microenvironment. These results suggest that blocking of the CXCLs-CXCR2 axis in tumor-stromal interactions could be a therapeutic approach against PDAC progression.

Bone marrow-derived fibroblasts are a functionally distinct stromal cell population in breast cancer.

Cancer-associated fibroblasts (CAFs) are highly prominent in breast tumors, but their functional heterogeneity and origin are still largely unresolved. We report that bone marrow (BM)-derived mesenchymal stromal cells (MSCs) are recruited to primary breast tumors and to lung metastases and differentiate to a distinct subpopulation of CAFs. We show that BM-derived CAFs are functionally important for tumor growth and enhance angiogenesis via up-regulation of Clusterin. Using newly generated transgenic mice and adoptive BM transplantations, we demonstrate that BM-derived fibroblasts are a substantial source of CAFs in the tumor microenvironment. Unlike resident CAFs, BM-derived CAFs do not express PDGFRα, and their recruitment resulted in a decrease in the percentage of PDGFRα-expressing CAFs. Strikingly, decrease in PDGFRα in breast cancer patients was associated with worse prognosis, suggesting that BM-derived CAFs may have deleterious effects on survival. Therefore, PDGFRα expression distinguishes two functionally unique CAF populations in breast tumors and metastases and may have important implications for patient stratification and precision therapeutics.

Phase 2 Trial of Ibudilast in Progressive Multiple Sclerosis.

BACKGROUND: There are limited treatments for progressive multiple sclerosis. Ibudilast inhibits several cyclic nucleotide phosphodiesterases, macrophage migration inhibitory factor, and toll-like receptor 4 and can cross the blood-brain barrier, with potential salutary effects in progressive multiple sclerosis. METHODS: We enrolled patients with primary or secondary progressive multiple sclerosis in a phase 2 randomized trial of oral ibudilast (≤100 mg daily) or placebo for 96 weeks. The primary efficacy end point was the rate of brain atrophy, as measured by the brain parenchymal fraction (brain size relative to the volume of the outer surface contour of the brain). Major secondary end points included the change in the pyramidal tracts on diffusion tensor imaging, the magnetization transfer ratio in normal-appearing brain tissue, the thickness of the retinal nerve-fiber layer, and cortical atrophy, all measures of tissue damage in multiple sclerosis. RESULTS: Of 255 patients who underwent randomization, 129 were assigned to ibudilast and 126 to placebo. A total of 53% of the patients in the ibudilast group and 52% of those in the placebo group had primary progressive disease; the others had secondary progressive disease. The rate of change in the brain parenchymal fraction was -0.0010 per year with ibudilast and -0.0019 per year with placebo (difference, 0.0009; 95% confidence interval, 0.00004 to 0.0017; P=0.04), which represents approximately 2.5 ml less brain-tissue loss with ibudilast over a period of 96 weeks. Adverse events with ibudilast included gastrointestinal symptoms, headache, and depression. CONCLUSIONS: In a phase 2 trial involving patients with progressive multiple sclerosis, ibudilast was associated with slower progression of brain atrophy than placebo but was associated with higher rates of gastrointestinal side effects, headache, and depression. (Funded by the National Institute of Neurological Disorders and Stroke and others; NN102/SPRINT-MS ClinicalTrials.gov number, NCT01982942 .).

Cladribine tablets added to IFN-ß in active relapsing MS: The ONWARD study.

OBJECTIVE: To evaluate the safety and efficacy of cladribine tablets in patients still experiencing active relapsing MS despite interferon (IFN)-ß treatment. METHODS: A 96-week phase II study, randomizing patients treated with IFN-ß to cladribine tablets 3.5 mg/kg/IFN-ß or placebo/IFN-ß. Patients were to receive cladribine tablets 3.5 mg/kg/IFN-ß or placebo/IFN-ß in a 2:1 ratio (n = 172) with safety and exploratory efficacy outcomes being assessed. RESULTS: Adverse events (AEs) and serious AEs were similar across treatment groups, except lymphopenia. Fifty of 124 (40.3%) cladribine/IFN-ß recipients vs 0% of placebo/IFN-ß recipients reported lymphopenia as an AE, with grade 3/4 lymphopenia (laboratory lymphocyte count < 500 cells/mm3) experienced by 79/124 (63.7%) vs 1 (2.1%), respectively. Patients treated with cladribine tablets 3.5 mg/kg/IFN-ß were 63% less likely to have a qualifying relapse than placebo/IFN-ß recipients, and cladribine tablets 3.5 mg/kg/IFN-ß reduced most MRI measures of disease activity. CONCLUSIONS: In patients with active relapsing MS despite IFN-ß treatment, cladribine tablets 3.5 mg/kg/IFN-ß reduced relapses and MRI lesion activity over 96 weeks compared with placebo/IFN-ß but led to an increased incidence of lymphopenia. CLASSIFICATION OF EVIDENCE: This study provides Class I evidence that for patients with active relapsing MS despite IFN-ß treatment, cladribine tablets added to IFN-ß reduced relapses and MRI lesion activity over 96 weeks and increased the incidence of lymphopenia. CLINICAL TRIAL REGISTRATION: NCT00436826.

Clinical outcomes in patients with relapsing-remitting multiple sclerosis who switch from natalizumab to delayed-release dimethyl fumarate: A multicenter retrospective observational study (STRATEGY).

BACKGROUND: Delayed-release dimethyl fumarate (DMF) may be a therapeutic option for patients with relapsing-remitting multiple sclerosis (RRMS) who are treated with natalizumab and require a change in therapy. However, there is limited information regarding predictors of favorable treatment outcomes in patients switching from natalizumab to DMF. Clinical practices and sequencing protocols vary. Herein, we present the clinical results, including annualized relapse rate (ARR) and risk of relapse, of a phase 4 retrospective observational study of patients with RRMS who switched from natalizumab to DMF in a community practice setting (STRATEGY). METHODS: STRATEGY was performed through a single time point medical record abstraction; no study visits or procedures were required. Key inclusion criteria included age ≥ 18 years, RRMS diagnosis (McDonald criteria, 2010 revised), ≥ 12 months of continuous treatment with natalizumab monotherapy before DMF initiation, and initiation of DMF ≥ 12 months before enrollment. Patients were eligible to enroll regardless of current DMF use. RESULTS: A total of 530 patients at 45 US sites enrolled, and 506 met the inclusion criteria and were included in the modified evaluable population for analysis. Mean (SD) age at DMF initiation was 47.0 (10.9) years, with a mean (SD) of 12.7 (7.2) years since MS diagnosis. The mean (SD) duration of natalizumab treatment was 3.4 (1.9) years, and the mean (SD) washout from natalizumab discontinuation to DMF initiation (n = 502) was 101.6 (164.0) days. Overall risk of relapse 12 months after DMF initiation was 19.6%. Overall unadjusted ARR was higher during the 12 months following initiation of DMF treatment compared with the 12 months following initiation of natalizumab treatment (rate ratio, 2.32 [95% CI, 1.69-3.18]; p < 0.0001), but was lower compared with that observed in the year before initiation of natalizumab (rate ratio, 0.51 [95% CI, 0.40-0.64]; p < 0.0001). At 1 year following initiation of DMF treatment, the relapse rate was lower for patients who did not experience a relapse during 1 year following initiation of natalizumab treatment than for those who did (rate ratio for relapse rate, 0.47 [95% CI, 0.16-1.38]; p = 0.1664). The relapse rate for patients who did not relapse during natalizumab treatment was significantly lower with a washout period of ≤ 90 days as compared with a washout period of > 90 days (rate ratio for relapse rate, 0.49 [95% CI, 0.26-0.90]; p = 0.0216). A total of 42 (8%) patients reported ≥ 1 adverse event leading to DMF discontinuation during the study; the most commonly reported events were gastrointestinal disorders (n = 21; 4%). CONCLUSIONS: Results from this multicenter retrospective observational study suggest that DMF may be an effective treatment option for patients who discontinue natalizumab in routine clinical practice. ARR was lower in patients who initiated DMF within 90 days of natalizumab discontinuation compared with patients who initiated DMF after 90 days of natalizumab discontinuation. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov identifier NCT02159573.

Infliximab for the treatment of CNS sarcoidosis: A multi-institutional series.

OBJECTIVE: To describe clinical and imaging responses in neurosarcoidosis to infliximab, a monoclonal antibody against tumor necrosis factor-α. METHODS: Investigators at 6 US centers retrospectively identified patients with CNS sarcoidosis treated with infliximab, including only patients with definite or probable neurosarcoidosis following rigorous exclusion of other causes. RESULTS: Of 66 patients with CNS sarcoidosis (27 definite, 39 probable) treated with infliximab for a median of 1.5 years, the mean age was 47.5 years at infliximab initiation (SD 11.7, range 24-71 years); 56.1% were female; 62.1% were white, 37.0% African American, and 3% Hispanic. Sarcoidosis was isolated to the CNS in 19.7%. Using infliximab doses ranging from 3 to 7 mg/kg every 4-8 weeks, MRI evidence of a favorable treatment response was observed in 82.1% of patients with imaging follow-up (n = 56), with complete remission of active disease in 51.8% and partial MRI improvement in 30.1%; MRI worsened in 1 patient (1.8%). There was clinical improvement in 77.3% of patients, with complete neurologic recovery in 28.8%, partial improvement in 48.5%, clinical stability in 18.2%, worsening in 3%, and 1 lost to follow-up. In 16 patients in remission when infliximab was discontinued, the disease recurred in 9 (56%), typically in the same neuroanatomic location. CONCLUSIONS: Most patients with CNS sarcoidosis treated with infliximab exhibit favorable imaging and clinical treatment responses, including some previously refractory to other immunosuppressive treatments. CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that for patients with CNS sarcoidosis infliximab is associated with favorable imaging and clinical responses.

Development of Aggressive Pancreatic Ductal Adenocarcinomas Depends on Granulocyte Colony Stimulating Factor Secretion in Carcinoma Cells.

The survival rate for pancreatic ductal adenocarcinoma (PDAC) remains low. More therapeutic options to treat this disease are needed, for the current standard of care is ineffective. Using an animal model of aggressive PDAC (Kras/p48TGFßRIIKO), we discovered an effect of TGFß signaling in regulation of G-CSF secretion in pancreatic epithelium. Elevated concentrations of G-CSF in PDAC promoted differentiation of Ly6G+ cells from progenitors, stimulated IL10 secretion from myeloid cells, and decreased T-cell proliferation via upregulation of Arg, iNOS, VEGF, IL6, and IL1b from CD11b+ cells. Deletion of csf3 in PDAC cells or use of a G-CSF-blocking antibody decreased tumor growth. Anti-G-CSF treatment in combination with the DNA synthesis inhibitor gemcitabine reduced tumor size, increased the number of infiltrating T cells, and decreased the number of Ly6G+ cells more effectively than gemcitabine alone. Human analysis of human datasets from The Cancer Genome Atlas and tissue microarrays correlated with observations from our mouse model experiments, especially in patients with grade 1, stage II disease. We propose that in aggressive PDAC, elevated G-CSF contributes to tumor progression through promoting increases in infiltration of neutrophil-like cells with high immunosuppressive activity. Such a mechanism provides an avenue for a neoadjuvant therapeutic approach for this devastating disease. Cancer Immunol Res; 5(9); 718-29. ©2017 AACR.

Pharmacologic Inhibition of ß-Catenin With Pyrvinium Inhibits Murine and Human Models of Wilms Tumor.

Wilms tumor (WT) is the most common renal malignancy in children and the fourth most common pediatric solid malignancy in the US. Although the mechanisms underlying the WT biology are complex, these tumors most often demonstrate activation of the canonical Wnt/ß-catenin pathway. We and others have shown that constitutive activation of ß-catenin restricted to the renal epithelium is sufficient to induce primitive renal epithelial tumors, which resemble human WT. Here we demonstrate that pharmacologic inhibition of ß-catenin gene transcription with pyrvinium inhibits tumor growth and metastatic progression in a murine model of WT. Cellular invasion is significantly inhibited in both murine WT-like and human WT cells and is accompanied by downregulation of the oncogenes Myc and Birc5 (survivin). Our studies provide proof of the concept that the canonical Wnt/ß-catenin pathway may be a novel therapeutic target in the management of WT.

Functional KRAS mutations and a potential role for PI3K/AKT activation in Wilms tumors.

Wilms tumor (WT) is the most common renal neoplasm of childhood and affects 1 in 10 000 children aged less than 15 years. These embryonal tumors are thought to arise from primitive nephrogenic rests that derive from the metanephric mesenchyme during kidney development and are characterized partly by increased Wnt/ß-catenin signaling. We previously showed that coordinate activation of Ras and ß-catenin accelerates the growth and metastatic progression of a murine WT model. Here, we show that activating KRAS mutations can be found in human WT. In addition, high levels of phosphorylated AKT are present in the majority of WT. We further show in a mouse model and in renal epithelial cells that Ras cooperates with ß-catenin to drive metastatic disease progression and promotes in vitro tumor cell growth, migration, and colony formation in soft agar. Cellular transformation and metastatic disease progression of WT cells are in part dependent on PI3K/AKT activation and are inhibited via pharmacological inhibition of this pathway. Our studies suggest both KRAS mutations and AKT activation are present in WT and may represent novel therapeutic targets for this disease.

TGF-ß, Bone Morphogenetic Protein, and Activin Signaling and the Tumor Microenvironment.

The cellular and noncellular components surrounding the tumor cells influence many aspects of tumor progression. Transforming growth factor ß (TGF-ß), bone morphogenetic proteins (BMPs), and activins have been shown to regulate the phenotype and functions of the microenvironment and are attractive targets to attenuate protumorigenic microenvironmental changes. Given the pleiotropic nature of the cytokines involved, a full understanding of their effects on numerous cell types in many contexts is necessary for proper clinical intervention. In this review, we will explore the various effects of TGF-ß, BMP, and activin signaling on stromal phenotypes known to associate with cancer progression. We will summarize these findings in the context of their tumor suppressive or promoting effects, as well as the molecular changes that these cytokines induce to influence stromal phenotypes.

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

Purpose: Metastatic breast cancers continue to elude current therapeutic strategies, including those utilizing PI3K inhibitors. Given the prominent role of PI3Kα,ß 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.