Enhanced antitumor immunity through sequential targeting of PI3Kδ and LAG3

Lauder, Sarah Nicol, Smart, Kathryn, Kersemans, Veerle, Allen, Danny, Scott, Jake, Pires, Ana, Milutinovic, Stefan ORCID: https://orcid.org/0000-0002-3163-3383, Somerville, Michelle, Smart, Sean, Kinchesh, Paul, Lopez-Guadamillas, Elena, Hughes, Ellyn, Jones, Emma, Scurr, Martin ORCID: https://orcid.org/0000-0002-4120-0688, Godkin, Andrew ORCID: https://orcid.org/0000-0002-1910-7567, Friedman, Lori S, Vanhaesebroeck, Bart and Gallimore, Awen ORCID: https://orcid.org/0000-0001-6675-7004 2020. Enhanced antitumor immunity through sequential targeting of PI3Kδ and LAG3. Journal for ImmunoTherapy of Cancer 8 (2) , e000693. 10.1136/jitc-2020-000693

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Abstract

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.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Medicine
Additional Information:	This is an open access article distributed in accordance with the Creative Commons Attribution 4.0 Unported (CC BY 4.0) license, which permits others to copy, redistribute, remix, transform and build upon this work for any purpose, provided the original work is properly cited, a link to the licence is given, and indication of whether changes were made. See https://creativecommons.org/licenses/by/4.0/.
Publisher:	BMJ
ISSN:	2051-1426
Funders:	Wellcome Trust, Cancer Research UK
Date of First Compliant Deposit:	28 October 2020
Date of Acceptance:	13 September 2020
Last Modified:	12 Oct 2023 04:34
URI:	https://orca.cardiff.ac.uk/id/eprint/136000

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