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
View: Text | PDF
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

×

Figure 9

PD-L1 blockade synergizes with CD40L to improve antigen-specific T cell expansion.

Options: View larger image (or click on image) Download as PowerPoint
PD-L1 blockade synergizes with CD40L to improve antigen-specific T cell ...
Immature Mo-DCs generated from healthy blood donors were either left untreated (control, Cntr) or treated with CD40L (250 ng/mL) alone (–) or with 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. (A) Anti–PD-L1 treatment synergizes with CD40L to improve DC maturation. Figure shows fold change in DC maturation (assessed by increase in CD83 and CD80 double-positive cells) compared with control cells. (B) Representative data from one donor showing increased DC maturation with concurrent treatment with CD40L and PD-L1. (C) Immature Mo-DCs (HLA-A2.1+) were stimulated with CD40L alone or CD40L plus anti–PD-L1 antibody. After overnight culture, DCs were loaded with HLA-A2.1-specific influenza matrix peptide (FMP) at 0.1 μg/mL and used to stimulate autologous T cells. After 10–12 days of DC–T cell coculture, expansion of influenza-specific T cells was analyzed using FMP-specific tetramer. (*P < 0.05, Kruskal Wallis test).