Phosphoinositide 3-kinase δ inhibition promotes antitumor responses but antagonizes checkpoint inhibitors

Phosphoinositide 3‐kinase δ is a regulatory T‐cell target in cancer immunotherapy

“…Whereas PI3K δ inhibition has been reported to preferentially incapacitate Treg cells over effector T cells in the anti‐tumour immune response, a different study has shown that loss of PI3K δ activity abrogates tumour elimination by CD8 + T cells, so the overall effect of PI3K δ inactivation on tumour growth may depend on a balance of the impact on effector and regulatory T‐cell subsets. We have demonstrated that enhancement of anti‐tumour immunity by PI3K δ inactivation occurs in spite of concurrent impairment of CD8 + T‐cell cytotoxicity, and correlates with the dependence of the tumour on Treg‐mediated immunosuppression . Supporting a requirement for PI3K δ activity in tumour Treg cell function, constitutive nuclear localization of Foxo1 – as would be the case in PI3K δ inactivation – blocks Treg cell tumour infiltration and boosts anti‐tumour immunity …”

“…We have demonstrated that enhancement of anti-tumour immunity by PI3Kd inactivation occurs in spite of concurrent impairment of CD8 + T-cell cytotoxicity, 69 and correlates with the dependence of the tumour on Treg-mediated immunosuppression. 70 would be the case in PI3Kd inactivationblocks Treg cell tumour infiltration and boosts anti-tumour immunity. 73 We therefore suggest that Treg cells have varying requirements for PI3Kd signalling throughout their lifespan, benefiting from reduced activity during development, but depending on the PI3Kd pathway in delivering immune suppression as mature regulators.…”

“…Additionally, we and others have shown that PI3K δ ‐inactivated Treg cells are impaired in mediating tumour immunosuppression. Loss of PI3K δ activity, especially by specific deletion in Treg cells, can restrict the growth of transplanted tumours in mice . Whereas PI3K δ inhibition has been reported to preferentially incapacitate Treg cells over effector T cells in the anti‐tumour immune response, a different study has shown that loss of PI3K δ activity abrogates tumour elimination by CD8 + T cells, so the overall effect of PI3K δ inactivation on tumour growth may depend on a balance of the impact on effector and regulatory T‐cell subsets.…”

“…Loss of PI3Kd activity, especially by specific deletion in Treg cells, can restrict the growth of transplanted tumours in mice. [69][70][71] Whereas PI3Kd inhibition has been reported to preferentially incapacitate Treg cells over effector T cells in the anti-tumour immune response, 59 a different study has shown that loss of PI3Kd activity abrogates tumour elimination by CD8 + T cells, 72 so the overall effect of PI3Kd inactivation on tumour growth may depend on a balance of the impact on effector and regulatory T-cell subsets. We have demonstrated that enhancement of anti-tumour immunity by PI3Kd inactivation occurs in spite of concurrent impairment of CD8 + T-cell cytotoxicity, 69 and correlates with the dependence of the tumour on Treg-mediated immunosuppression.…”

“…110,112,113 Like conventional T cells, Treg cells lacking PD-1 show enhanced proliferation; however, PD-1-deficient Treg cells have reduced expression of Bcl2, and may have reduced viability or stability. 114 Intriguingly, PI3Kddeficient tumour-infiltrating Treg cellsbut not CD8 + T cellsexpress markedly lower levels of PD-1 than PI3Kdsufficient controls; 70 whether a consequent loss of Treg cell stability can explain the anti-tumour effects of PI3Kd inactivation remains to be determined. Mice with inactive PI3Kd become unresponsive to anti-CTLA-4 or anti-PD-L1 treatment, even in tumour models that are usually sensitive to checkpoint blockade.…”