Lauder et al. demonstrated that the antitumor immunity of PI3Kδ-targeted immunotherapy in the 4T1 tumor model was CD8+ T cell-dependent and that tumors could be divided into regressors and non-regressors. In the regressor group, PI3Kδ inhibition increased TCF1-expressing CD4+ and CD8+ TILs with enhanced metabolic fitness, increased tumor-specific CD8+ T cells, and decreased CD69+ CD8+ T cells. Following PI3Kδ inhibition, LAG3 and CD69 expression increased in FoxP3+ Treg in non-regressor tumors. PI3Kδ and LAG3 inhibition combination decreased tumor growth in 4T1 and CT26 tumor models, but not in MC38 tumors.
Contributed by Shishir Pant
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 PI3K_ inhibition therapy. Follow-up studies, performed using additional cancer cell lines, namely MC38 and CT26, indicated that a partial initial response to PI3K_ 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.
Author Info: (1) Infection and Immunity, Cardiff University Department of Medicine, Cardiff, UK LauderSN@cardiff.ac.uk. (2) Infection and Immunity, Cardiff University Department of Medicine, Ca
Author Info: (1) Infection and Immunity, Cardiff University Department of Medicine, Cardiff, UK LauderSN@cardiff.ac.uk. (2) Infection and Immunity, Cardiff University Department of Medicine, Cardiff, UK. (3) Infection and Immunity, University of Oxford, Oxford, UK. (4) CRUK/MRC Oxford Institute for Radiation Oncology, Department of Oncology, University of Oxford, Oxford, UK. (5) Infection and Immunity, Cardiff University Department of Medicine, Cardiff, UK. (6) Infection and Immunity, Cardiff University Department of Medicine, Cardiff, UK. (7) Infection and Immunity, Cardiff University Department of Medicine, Cardiff, UK. (8) Infection and Immunity, Cardiff University Department of Medicine, Cardiff, UK. (9) CRUK/MRC Oxford Institute for Radiation Oncology, Department of Oncology, University of Oxford, Oxford, UK. (10) CRUK/MRC Oxford Institute for Radiation Oncology, Department of Oncology, University of Oxford, Oxford, UK. (11) UCL Cancer Institute, Paul O'Gorman Building, University College London, London, UK. (12) Cancer Biomarker Group, Cancer Research UK Manchester Institute, The University of Manchester, Manchester, UK. (13) Infection and Immunity, Cardiff University Department of Medicine, Cardiff, UK. (14) Infection and Immunity, Cardiff University Department of Medicine, Cardiff, UK. (15) Infection and Immunity, Cardiff University Department of Medicine, Cardiff, UK. (16) ORIC Pharmaceuticals, South San Francisco, California, USA. (17) UCL Cancer Institute, Paul O'Gorman Building, University College London, London, UK. (18) Infection and Immunity, Cardiff University Department of Medicine, Cardiff, UK.
