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 5

Changes in circulating T cells following therapy with anti–PD-L1 in asymptomatic myeloma (AMM).

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Changes in circulating T cells following therapy with anti–PD-L1 in asym...
PBMCs isolated from blood of AMM patients before therapy (PreC1) and following therapy with atezolizumab on day 15 (C1D15), as well as before cycles 2–7 (C2–C7), were analyzed using single cell mass cytometry or CyTOF. (A) Changes in CD4 and CD8 naive and memory T cells during therapy with atezolizumab. Data are shown as fold change compared with levels before starting therapy (PreC1). (B) Ki-67+ proliferating naive (CCR7+RO–), central memory (Tcm; CCR7+RO+), and effector memory (Tem; CCR7–RO+) T cells before (Pre), 15 days following start of therapy (C1D15), and before cycle 2 (C1D21) of therapy with atezolizumab. Figure shows data from 2 separate patients. (C) PBMCs obtained pre therapy (PreC1), 15 days after starting therapy (C1D15), or before cycles 2–7 (C2-C7) were evaluated for the presence of SOX2-specific T cell reactivity using overlapping peptides encompassing the entire SOX2 antigen as previously described (10). Figure shows SOX2 T cell reactivity in the 2 patients. Data reported as fold change compared with before therapy (PreC1) for SOX2 reactive submix versus nonreactive mix as control.