Enhanced antitumor immunity through sequential targeting of PI3Kδ and LAG3
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...
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| Format: | Article |
| Language: | English |
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BMJ Publishing Group
2020-10-01
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| Series: | Journal for ImmunoTherapy of Cancer |
| Online Access: | https://jitc.bmj.com/content/8/2/e000693.full |
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| _version_ | 1846171308311707648 |
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| author | Emma Jones Andrew Godkin Sarah Nicol Lauder Kathryn Smart Veerle Kersemans Danny Allen Jake Scott Ana Pires Stefan Milutinovic Michelle Somerville Sean Smart Paul Kinchesh Elena Lopez-Guadamillas Ellyn Hughes Martin Scurr Lori S Friedman Bart Vanhaesebroeck Awen Gallimore |
| author_facet | Emma Jones Andrew Godkin Sarah Nicol Lauder Kathryn Smart Veerle Kersemans Danny Allen Jake Scott Ana Pires Stefan Milutinovic Michelle Somerville Sean Smart Paul Kinchesh Elena Lopez-Guadamillas Ellyn Hughes Martin Scurr Lori S Friedman Bart Vanhaesebroeck Awen Gallimore |
| author_sort | Emma Jones |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-03253b8693d64d3c84a6f9eeb342088e |
| institution | Kabale University |
| issn | 2051-1426 |
| language | English |
| publishDate | 2020-10-01 |
| publisher | BMJ Publishing Group |
| record_format | Article |
| series | Journal for ImmunoTherapy of Cancer |
| spelling | doaj-art-03253b8693d64d3c84a6f9eeb342088e2024-11-10T23:30:08ZengBMJ Publishing GroupJournal for ImmunoTherapy of Cancer2051-14262020-10-018210.1136/jitc-2020-000693Enhanced antitumor immunity through sequential targeting of PI3Kδ and LAG3Emma Jones0Andrew Godkin1Sarah Nicol Lauder2Kathryn Smart3Veerle Kersemans4Danny Allen5Jake Scott6Ana Pires7Stefan Milutinovic8Michelle Somerville9Sean Smart10Paul Kinchesh11Elena Lopez-Guadamillas12Ellyn Hughes13Martin Scurr14Lori S Friedman15Bart Vanhaesebroeck16Awen Gallimore171 Clinical Trials Unit, University of Warwick, Coventry, UK1Cardiff University1 Infection and Immunity, Cardiff University Department of Medicine, Cardiff, UK1 Infection and Immunity, Cardiff University Department of Medicine, Cardiff, UK2 Infection and Immunity, University of Oxford, Oxford, UK3 CRUK/MRC Oxford Institute for Radiation Oncology, Department of Oncology, University of Oxford, Oxford, UKclinical assistant professor1 Infection and Immunity, Cardiff University Department of Medicine, Cardiff, UK1 Infection and Immunity, Cardiff University Department of Medicine, Cardiff, UK1 Infection and Immunity, Cardiff University Department of Medicine, Cardiff, UK3 CRUK/MRC Oxford Institute for Radiation Oncology, Department of Oncology, University of Oxford, Oxford, UK3 CRUK/MRC Oxford Institute for Radiation Oncology, Department of Oncology, University of Oxford, Oxford, UK4 UCL Cancer Institute, Paul O`Gorman Building, University College London, London, UK5 Cancer Biomarker Group, Cancer Research UK Manchester Institute, The University of Manchester, Manchester, UK1 Infection and Immunity, Cardiff University Department of Medicine, Cardiff, UK6 ORIC Pharmaceuticals, South San Francisco, California, USA1UCL Cancer Institute, Pre-Cancer Immunology Laboratory, London, UK1 Infection and Immunity, Cardiff University Department of Medicine, Cardiff, UKBackground 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.https://jitc.bmj.com/content/8/2/e000693.full |
| spellingShingle | Emma Jones Andrew Godkin Sarah Nicol Lauder Kathryn Smart Veerle Kersemans Danny Allen Jake Scott Ana Pires Stefan Milutinovic Michelle Somerville Sean Smart Paul Kinchesh Elena Lopez-Guadamillas Ellyn Hughes Martin Scurr Lori S Friedman Bart Vanhaesebroeck Awen Gallimore Enhanced antitumor immunity through sequential targeting of PI3Kδ and LAG3 Journal for ImmunoTherapy of Cancer |
| title | Enhanced antitumor immunity through sequential targeting of PI3Kδ and LAG3 |
| title_full | Enhanced antitumor immunity through sequential targeting of PI3Kδ and LAG3 |
| title_fullStr | Enhanced antitumor immunity through sequential targeting of PI3Kδ and LAG3 |
| title_full_unstemmed | Enhanced antitumor immunity through sequential targeting of PI3Kδ and LAG3 |
| title_short | Enhanced antitumor immunity through sequential targeting of PI3Kδ and LAG3 |
| title_sort | enhanced antitumor immunity through sequential targeting of pi3kδ and lag3 |
| url | https://jitc.bmj.com/content/8/2/e000693.full |
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