RT Journal Article
SR Electronic
T1 Enhanced antitumor immunity through sequential targeting of PI3Kδ and LAG3
JF Journal for ImmunoTherapy of Cancer
JO J Immunother Cancer
FD BMJ Publishing Group Ltd
SP e000693
DO 10.1136/jitc-2020-000693
VO 8
IS 2
A1 Sarah Nicol Lauder
A1 Kathryn Smart
A1 Veerle Kersemans
A1 Danny Allen
A1 Jake Scott
A1 Ana Pires
A1 Stefan Milutinovic
A1 Michelle Somerville
A1 Sean Smart
A1 Paul Kinchesh
A1 Elena Lopez-Guadamillas
A1 Ellyn Hughes
A1 Emma Jones
A1 Martin Scurr
A1 Andrew Godkin
A1 Lori S Friedman
A1 Bart Vanhaesebroeck
A1 Awen Gallimore
YR 2020
UL http://jitc.bmj.com/content/8/2/e000693.abstract
AB Background Despite striking successes, immunotherapies aimed at increasing cancer-specific T cell responses are unsuccessful in most patients with cancer. Inactivating regulatory T cells (Treg) by inhibiting the PI3Kδ signaling enzyme has shown promise in preclinical models of tumor immunity and is currently being tested in early phase clinical trials in solid tumors.Methods Mice bearing 4T1 mammary tumors were orally administered a PI3Kδ inhibitor (PI-3065) daily and tumor growth, survival and T cell infiltrate were analyzed in the tumor microenvironment. A second treatment schedule comprised PI3Kδ inhibitor with anti-LAG3 antibodies administered sequentially 10 days later.Results As observed in human immunotherapy trials with other agents, immunomodulation by PI3Kδ-blockade led to 4T1 tumor regressor and non-regressor mice. Tumor infiltrating T cells in regressors were metabolically fitter than those in non-regressors, with significant enrichments of antigen-specific CD8+ T cells, T cell factor 1 (TCF1)+ T cells and CD69− T cells, compatible with induction of a sustained tumor-specific T cell response. Treg numbers were significantly reduced in both regressor and non-regressor tumors compared with untreated tumors. The remaining Treg in non-regressor tumors were however significantly enriched with cells expressing the coinhibitory receptor LAG3, compared with Treg in regressor and untreated tumors. This striking difference prompted us to sequentially block PI3Kδ and LAG3. This combination enabled successful therapy of all mice, demonstrating the functional importance of LAG3 in non-regression of tumors on PI3Kδ inhibition therapy. Follow-up studies, performed using additional cancer cell lines, namely MC38 and CT26, indicated that a partial initial response to PI3Kδ inhibition is an essential prerequisite to a sequential therapeutic benefit of anti-LAG3 antibodies.Conclusions These data indicate that LAG3 is a key bottleneck to successful PI3Kδ-targeted immunotherapy and provide a rationale for combining PI3Kδ/LAG3 blockade in future clinical studies.