BACKGROUNDPD-1 and PD-L1 have been studied interchangeably in the clinic as checkpoints to reinvigorate T cells in diverse tumor types. Data for biologic effects of checkpoint blockade in human premalignancy are limited.METHODSWe analyzed the immunologic effects of PD-L1 blockade in a clinical trial of atezolizumab in patients with asymptomatic multiple myeloma (AMM), a precursor to clinical malignancy. Genomic signatures of PD-L1 blockade in purified monocytes and T cells in vivo were also compared with those following PD-1 blockade in lung cancer patients. Effects of PD-L1 blockade on monocyte-derived DCs were analyzed to better understand its effects on myeloid antigen-presenting cells.RESULTSIn contrast to anti-PD-1 therapy, anti-PD-L1 therapy led to a distinct inflammatory signature in CD14+ monocytes and increase in myeloid-derived cytokines (e.g., IL-18) in vivo. Treatment of AMM patients with atezolizumab led to rapid activation and expansion of circulating myeloid cells, which persisted in the BM. Blockade of PD-L1 on purified monocyte-derived DCs led to rapid inflammasome activation and synergized with CD40L-driven DC maturation, leading to greater antigen-specific T cell expansion.CONCLUSIONThese data show that PD-L1 blockade leads to distinct systemic immunologic effects compared with PD-1 blockade in vivo in humans, particularly manifest as rapid myeloid activation. These findings also suggest an additional role for PD-L1 as a checkpoint for regulating inflammatory phenotype of myeloid cells and antigen presentation in DCs, which may be harnessed to improve PD-L1-based combination therapies.TRIAL REGISTRATIONNCT02784483.FUNDINGThis work is supported, in part, by funds from NIH/NCI (NCI CA197603, CA238471, and CA208328).

Differential effects of PD-L1 versus PD-1 blockade on myeloid inflammation in human cancer / Bar, N.; Costa, F.; Das, R.; Duffy, A.; Samur, M.; Mccachren, S.; Gettinger, S. N.; Neparidze, N.; Parker, T. L.; Bailur, J. K.; Pendleton, K.; Bajpai, R.; Zhang, L.; Xu, M. L.; Anderson, T.; Giuliani, N.; Nooka, A.; Cho, H. J.; Raval, A.; Shanmugam, M.; Dhodapkar, K. M.; Dhodapkar, M. V.. - In: JCI INSIGHT. - ISSN 2379-3708. - 5:12(2020). [10.1172/jci.insight.129353]

Differential effects of PD-L1 versus PD-1 blockade on myeloid inflammation in human cancer

Giuliani N.;
2020-01-01

Abstract

BACKGROUNDPD-1 and PD-L1 have been studied interchangeably in the clinic as checkpoints to reinvigorate T cells in diverse tumor types. Data for biologic effects of checkpoint blockade in human premalignancy are limited.METHODSWe analyzed the immunologic effects of PD-L1 blockade in a clinical trial of atezolizumab in patients with asymptomatic multiple myeloma (AMM), a precursor to clinical malignancy. Genomic signatures of PD-L1 blockade in purified monocytes and T cells in vivo were also compared with those following PD-1 blockade in lung cancer patients. Effects of PD-L1 blockade on monocyte-derived DCs were analyzed to better understand its effects on myeloid antigen-presenting cells.RESULTSIn contrast to anti-PD-1 therapy, anti-PD-L1 therapy led to a distinct inflammatory signature in CD14+ monocytes and increase in myeloid-derived cytokines (e.g., IL-18) in vivo. Treatment of AMM patients with atezolizumab led to rapid activation and expansion of circulating myeloid cells, which persisted in the BM. Blockade of PD-L1 on purified monocyte-derived DCs led to rapid inflammasome activation and synergized with CD40L-driven DC maturation, leading to greater antigen-specific T cell expansion.CONCLUSIONThese data show that PD-L1 blockade leads to distinct systemic immunologic effects compared with PD-1 blockade in vivo in humans, particularly manifest as rapid myeloid activation. These findings also suggest an additional role for PD-L1 as a checkpoint for regulating inflammatory phenotype of myeloid cells and antigen presentation in DCs, which may be harnessed to improve PD-L1-based combination therapies.TRIAL REGISTRATIONNCT02784483.FUNDINGThis work is supported, in part, by funds from NIH/NCI (NCI CA197603, CA238471, and CA208328).
2020
Differential effects of PD-L1 versus PD-1 blockade on myeloid inflammation in human cancer / Bar, N.; Costa, F.; Das, R.; Duffy, A.; Samur, M.; Mccachren, S.; Gettinger, S. N.; Neparidze, N.; Parker, T. L.; Bailur, J. K.; Pendleton, K.; Bajpai, R.; Zhang, L.; Xu, M. L.; Anderson, T.; Giuliani, N.; Nooka, A.; Cho, H. J.; Raval, A.; Shanmugam, M.; Dhodapkar, K. M.; Dhodapkar, M. V.. - In: JCI INSIGHT. - ISSN 2379-3708. - 5:12(2020). [10.1172/jci.insight.129353]
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11381/2878970
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