Neutrophil content predicts lymphocyte depletion and anti-PD1 treatment failure in NSCLC
| Autor: | A. McGarry Houghton, Melissa Shipley, Jill McKay-Fleisch, Afshin Mashadi-Hossein, Gavin Meredith, Julia Kargl, John A. Zebala, Robert H. Pierce, Grace H. Y. Yang, Jeffrey C. Thompson, Dean Y. Maeda, Huajia Zhang, Steven M. Albelda, Xiaodong Zhu, Christina S. Baik, Hamid Bolouri, Mary W. Redman, Travis J. Friesen |
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| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Male Cell type Myeloid Lung Neoplasms Neutrophils medicine.medical_treatment T cell Programmed Cell Death 1 Receptor Datasets as Topic CD8-Positive T-Lymphocytes Receptors Interleukin-8B Flow cytometry Receptors Interleukin-8A Cohort Studies 03 medical and health sciences Leukocyte Count Mice 0302 clinical medicine Antineoplastic Agents Immunological Lymphocytes Tumor-Infiltrating Carcinoma Non-Small-Cell Lung medicine Animals Humans Treatment Failure Aged medicine.diagnostic_test business.industry Gene Expression Profiling General Medicine Immunotherapy Middle Aged medicine.disease Flow Cytometry Immunohistochemistry Disease Models Animal 030104 developmental biology medicine.anatomical_structure 030220 oncology & carcinogenesis Cancer research Female business CD8 Progressive disease Research Article |
| Zdroj: | JCI insight. 4(24) |
| ISSN: | 2379-3708 |
| Popis: | Immune checkpoint inhibitor (ICI) treatment has recently become a first-line therapy for many non–small cell lung cancer (NSCLC) patients. Unfortunately, most NSCLC patients are refractory to ICI monotherapy, and initial attempts to address this issue with secondary therapeutics have proven unsuccessful. To identify entities precluding CD8(+) T cell accumulation in this process, we performed unbiased analyses on flow cytometry, gene expression, and multiplexed immunohistochemical data from a NSCLC patient cohort. The results revealed the presence of a myeloid-rich subgroup, which was devoid of CD4(+) and CD8(+) T cells. Of all myeloid cell types assessed, neutrophils were the most highly associated with the myeloid phenotype. Additionally, the ratio of CD8(+) T cells to neutrophils (CD8/PMN) within the tumor mass optimally distinguished between active and myeloid cases. This ratio was also capable of showing the separation of patients responsive to ICI therapy from those with stable or progressive disease in 2 independent cohorts. Tumor-bearing mice treated with a combination of anti-PD1 and SX-682 (CXCR1/2 inhibitor) displayed relocation of lymphocytes from the tumor periphery into a malignant tumor, which was associated with induction of IFN-γ–responsive genes. These results suggest that neutrophil antagonism may represent a viable secondary therapeutic strategy to enhance ICI treatment outcomes. |
| Databáze: | OpenAIRE |
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