Differential effects of PD-L1 versus PD-1 blockade on myeloid inflammation in human cancer
| العنوان: | Differential effects of PD-L1 versus PD-1 blockade on myeloid inflammation in human cancer |
|---|---|
| المؤلفون: | Rituparna Das, Lin Zhang, Noffar Bar, Federica Costa, Hearn J. Cho, Scott N. Gettinger, Nicola Giuliani, Jithendra Kini Bailur, Natalia Neparidze, Katherine E. Pendleton, Mala Shanmugam, Samuel S. McCachren, Aparna Raval, Mina L. Xu, Ajay K. Nooka, Mehmet Kemal Samur, Richa Bajpai, Alyssa Duffy, Terri L. Parker, Kavita M. Dhodapkar, Madhav V. Dhodapkar, Tara Anderson |
| المصدر: | JCI Insight |
| بيانات النشر: | American Society for Clinical Investigation, 2020. |
| سنة النشر: | 2020 |
| مصطلحات موضوعية: | 0301 basic medicine, Lung Neoplasms, Myeloid, T cell, CD14, medicine.medical_treatment, Programmed Cell Death 1 Receptor, Antigen-Presenting Cells, Antibodies, Monoclonal, Humanized, B7-H1 Antigen, 03 medical and health sciences, 0302 clinical medicine, Cancer immunotherapy, Atezolizumab, PD-L1, Humans, Medicine, Inflammation, biology, business.industry, Antibodies, Monoclonal, Inflammasome, General Medicine, Blockade, 030104 developmental biology, medicine.anatomical_structure, 030220 oncology & carcinogenesis, Cancer research, biology.protein, Immunotherapy, Clinical Medicine, Multiple Myeloma, business, medicine.drug |
| الوصف: | 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). |
| تدمد: | 2379-3708 0278-4483 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::4d1d511b19d4ca884124c4fe4e31a4ceTest https://doi.org/10.1172/jci.insight.129353Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....4d1d511b19d4ca884124c4fe4e31a4ce |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 23793708 02784483 |
|---|