PI3K? is essential for tumor clearance mediated by cytotoxic T lymphocytes.

ABSTRACT:

Background

PI3K? is a lipid kinase of the phosphoinositide 3-kinase class 1A family and involved in early signaling events of leukocytes regulating proliferation, differentiation and survival. Currently, several inhibitors of PI3K? are under investigation for the treatment of hematopoietic malignancies. In contrast to the beneficial effect of inhibiting PI3K? in tumor cells, several studies reported the requirement of PI3K? for the function of immune cells, such as natural killer and T helper cells. Cytotoxic T lymphocytes (CTLs) are essential for tumor surveillance. The scope of this study is to clarify the potential impact of PI3K? inhibition on the function of CTLs with emphasis on tumor surveillance.

Principal findings

PI3K?-deficient mice develop significantly bigger tumors when challenged with MC38 colon adenocarcinoma cells. This defect is accounted for by the fact that PI3K? controls the secretory perforin-granzyme pathway as well as the death-receptor pathway of CTL-mediated cytotoxicity, leading to severely diminished cytotoxicity against target cells in vitro and in vivo in the absence of PI3K? expression. PI3K?-deficient CTLs express low mRNA levels of important components of the cytotoxic machinery, e.g. prf1, grzmA, grzmB, fasl and trail. Accordingly, PI3K?-deficient tumor-infiltrating CTLs display a phenotype reminiscent of naïve T cells (CD69(low)CD62L(high)). In addition, electrophysiological capacitance measurements confirmed a fundamental degranulation defect of PI3K?-/- CTLs.

Conclusion

Our results demonstrate that CTL-mediated tumor surveillance is severely impaired in the absence of PI3K? and predict that impaired immunosurveillance may limit the effectiveness of PI3K? inhibitors in long-term treatment.

SUBMITTER: Putz EM 

PROVIDER: S-EPMC3396622 | biostudies-literature | 2012

REPOSITORIES: biostudies-literature