Differential effects of PD-L1 versus PD-1 blockade on myeloid inflammation in human cancer
Noffar Bar, Federica Costa, Rituparna Das, Alyssa Duffy, Mehmet Samur, Samuel McCachren, Scott N. Gettinger, Natalia Neparidze, Terri L. Parker, Jithendra Kini Bailur, Katherine Pendleton, Richa Bajpai, Lin Zhang, Mina L. Xu, Tara Anderson, Nicola Giuliani, Ajay Nooka, Hearn J. Cho, Aparna Raval, Mala Shanmugam, Kavita M. Dhodapkar, Madhav V. Dhodapkar
Noffar Bar, Federica Costa, Rituparna Das, Alyssa Duffy, Mehmet Samur, Samuel McCachren, Scott N. Gettinger, Natalia Neparidze, Terri L. Parker, Jithendra Kini Bailur, Katherine Pendleton, Richa Bajpai, Lin Zhang, Mina L. Xu, Tara Anderson, Nicola Giuliani, Ajay Nooka, Hearn J. Cho, Aparna Raval, Mala Shanmugam, Kavita M. Dhodapkar, Madhav V. Dhodapkar
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Clinical Research and Public Health Hematology Immunology

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

Abstract

BACKGROUND PD-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.METHODS We 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.RESULTS In 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.CONCLUSION These 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 REGISTRATION NCT02784483.FUNDING This work is supported, in part, by funds from NIH/NCI (NCI CA197603, CA238471, and CA208328).

Authors

Noffar Bar, Federica Costa, Rituparna Das, Alyssa Duffy, Mehmet Samur, Samuel McCachren, Scott N. Gettinger, Natalia Neparidze, Terri L. Parker, Jithendra Kini Bailur, Katherine Pendleton, Richa Bajpai, Lin Zhang, Mina L. Xu, Tara Anderson, Nicola Giuliani, Ajay Nooka, Hearn J. Cho, Aparna Raval, Mala Shanmugam, Kavita M. Dhodapkar, Madhav V. Dhodapkar

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Figure 8

PD-L1 blockade leads to functional changes in DCs.

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PD-L1 blockade leads to functional changes in DCs. Immature Mo-DCs gener...
Immature Mo-DCs generated from healthy blood donors were either left untreated (control, Cntr) or treated with either anti–PD-L1 antibody (200 μg/mL), anti–PD-1 antibody (200 μg/mL), or their respective isotype control antibodies (Ig-G2b and Ig-G1) at 200 μg/mL or CD40L (250 ng/mL). Culture supernatants were analyzed for changes in cytokines using Luminex assay. Representative data from 7 healthy donors (HDs). (A) DC maturation following treatment with either anti–PD-L1, anti–PD-1, or isotype control. Figure shows fold change in CD83 and CD80 double-positive DCs compared with untreated cells. (B) Changes in secreted IL-8, IL-6, TNF-α, and IL-1β following treatment with anti–PD-L1 or anti–PD-1. (C) Treatment with anti–PD-L1 leads to early activation of caspase-1. Fold change of activated caspase-1 in immature Mo-DCs following treatment with anti–PD-L1 or anti–PD-1 for 4 hours. Figure shows fold change compared with untreated cells (Cntr). (D) Changes in respiratory capacity of DCs following treatment with anti–PD-L1. Immature Mo-DCs (n = 3 HDs) were either left untreated (control; Cntr) or were treated with anti–PD-L1 (200 μg/mL for 3 hours), and their spare respiratory capacity was analyzed using Seahorse XFe96 analyzer. Basal, coupled, maximal, and spare respiratory capacities were analyzed. Line graph shows data from a representative patient. Bar graph on the right shows data from all 3 different donors (mean ± SEM). (*P < 0.05, **P < 0.01, ***P < 0.001; A, C, D used Mann-Whitney U test, and B used Kruskal Wallis test).