Loss of tumor suppressor PTEN function increases B7-H1 expression and immunoresistance in glioma

Abstract

Cancer immunoresistance and immune escape may play important roles in tumor progression and pose obstacles for immunotherapy. Expression of the immunosuppressive protein B7 homolog 1 (B7-H1), also known as programmed death ligand-1 (PD-L1), is increased in many pathological conditions, including cancer. Here we show that expression of the gene encoding B7-H1 increases post transcriptionally in human glioma after loss of phosphatase and tensin homolog (PTEN) and activation of the phosphatidylinositol-3-OH kinase (PI(3)K) pathway. Tumor specimens from individuals with glioblastoma multiforme (GBM) had levels of B7-H1 protein that correlated with PTEN loss, and tumor-specific T cells lysed human glioma targets expressing wild-type PTEN more effectively than those expressing mutant PTEN. These data identify a previously unrecognized mechanism linking loss of the tumor suppressor PTEN with immunoresistance, mediated in part by B7-H1.

Clinicopathologic analysis of programmed cell death-1 and programmed cell death-ligand 1 and 2 expressions in pulmonary adenocarcinoma: comparison with histology and driver oncogenic alteration status

“…6,34 During antitumor immune responses in vivo, various immune and tumor cells produce cytokines that upregulate PD-L1 (CD274) extrinsically in a paracrine and/or autocrine manner. 6,35 In contrast, an intrinsic mechanism refers to constitutive PD-L1 expression by oncogenic signaling, such as NPM-ALK translocation, PI3K/Akt activation, or chronic viral infection, 26,34,36 suggesting that intrinsic genetic alterations in tumor cells might account for regulation of the PD-1/PD-L pathway. Moreover, several driver mutations have emerged as therapeutic targets for patients with pulmonary adenocarcinoma.…”

Targeting the function of the HER2 oncogene in human cancer therapeutics

“…Although these data sets are complicated by the concomitant use of cytotoxic chemotherapy regimens, they are the only currently existing evidence linking intracellular signaling with the clinical antitumor activity of trastuzumab. An association between trastuzumab resistance and PTEN loss by itself does not necessarily imply that trastuzumab inhibits tumors through direct effects on tumor signaling, since PTEN loss has also been shown to mediate immunoresistance (Parsa et al, 2007).…”

Decreased rate of infection in glioblastoma patients with allelic loss of chromosome 10q

“…First, DBMT1 may attract tumor-infiltrating macrophages: its loss may impair microglial infiltration into gliomas [9]. Second, disruption of PTEN (phosphatase and tensin homologue deleted in chromosome 10) may increase expression of immunosuppressive protein B7-H1 [10] and also increases Th2-inducing cytokine release [11,12]. While the former might impair antitumor cellular immunity in patients with LOH on chromosome 10q, a consideration for immunotherapy, the latter could cause 10q-maintaining tumor patients to experience increased bacterial infections, a source of morbidity and mortality in glioblastoma patients.…”

“…Specifically, we sought to determine if tumor LOH of 10q, which has previously been shown to impair the cellular immune response to malignant gliomas [10], might be associated with increased systemic humoral immunity, as manifested by a reduced incidence of systemic infections.…”