PI3Kδ inhibition enhances immune responses to a broad range of cancers

PI3Kδ inhibition has demonstrated remarkable therapeutic efficacy in blood cancers. The FDA has approved Gilead’s idelalisib for the treatment of relapsed chronic lymphocytic leukemia (CLL) and relapsed non-Hodgkin’s lymphoma.

However, PI3Kδ inhibitors have not previously been considered for the treatment of solid tumours, because p110δ is primarily expressed in white blood cells. A recent letter in Nature[1] with two comments[2, 3] suggest that such drugs could enhance immune responses to a broad range of cancers.

Compared to wild-type mice, δD910A mice, in which endogenous p110δ kinase is inactive, were more resistant to B16 melanoma, Lewis lung carcinoma, EL4 thymoma, and 4T1 breast cancer. In the case of 4T1 breast cancer, δD910A mice survival longer than wild-type mice (40 days vs. 23 days).

δD910A mice show impaired function of immune-suppressive regulatory T cells (Treg)[4]. The authors demonstrated that reduced Treg function in δD910A mice lead to enhanced tumour resistance. Moreover, PI3Kδ inhibition not only reduces the number of Treg cells but also impairs the function of myeloid-derived suppressor cells (MDSCs) to limit T-cell proliferation.

Finally, the authors investigated a small-molecule PI3Kδ inhibitor, PI-3065, in 4T1 breast cancer and pancreatic ductal adenocarcinoma. PI-3065 suppressed tumour growth and metastasis, and prolonged survival in these animals.

More interestingly, 4T1 cells do not express detectable levels of p110δ and are not growth-inhibited in vitro by PI-3065. However, PI-3065 suppressed 4T1 tumour growth and metastasis in vivo, to a similar extent as genetic inactivation of p110δ.

This paper provides a rationale for PI3Kδ inhibitors both in solid and blood cancers, possibly as an adjuvant to cancer vaccines, adoptive cell therapy, or other strategies that promote tumour-specific immune responses.

[1] Nature. 2014, 510(7505), 407-411.

[2] Nature. 2014, 510(7505), 342-343.

[3] Nat Rev Drug Discov. 2014, 13, 573-573.

[4] J Immunol. 2006, 177, 6598-6602.

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