Neutrophil abundance reduces response to immune checkpoint inhibitors

From the Houghton laboratory, Clinical Research Division

Lung cancer is the leading cause of cancer-related deaths worldwide. Immune checkpoint inhibitors (ICI), such as PD-1 inhibitors, have recently become first line therapies for lung cancer patients, including those with non-small cell lung cancer (NSCLC). While ICI have improved the clinical outcome for some patients, the majority of NSCLC patients either do not respond to ICI or develop resistance. Researchers from the Houghton lab (Clinical Research Division) sought to better understand why some patients respond well and others don’t. Their investigations were recently published in JCI Insight.

T lymphocytes (or T cells) are a class of immune cells that play an important role in the clearance of lung tumors. Previous research analyzing gene expression in the tumor noted that a “lymphocyte-depleted” environment is associated with a poorer prognosis. However, many of these environments contain large numbers of non-lymphocyte immune cells from the myeloid lineage. Standard gene expression profiling limits the amount of information we can gain on these immune cells, as many myeloid cell types are relatively transcriptionally quiet. Dr. McGarry Houghton and members of his group sought to overcome this challenge by using a combination of flow cytometry, gene expression, and multiplexed immunohistochemistry (IHC), which allowed them to better classify immune cells by their surface protein and gene expression. The authors used unbiased analysis of flow cytometry data from 68 NSCLC patients treated with ICI to classify distinct immune cell subsets found in the tumor and tumor-adjacent tissue. This allowed them to group patients by their immune infiltrate status. 10 cases displayed an “Inert” phenotype, defined by a lack of immune cell infiltrates, and these were excluded from further analysis. The other cases were classified into one of three categories: Active (increased T cell infiltrate), Myeloid (increased myeloid cell infiltrate), and Indeterminate (increased Th17 family cytokines).

Neutrophils found in the lung inhibit response to immune checkpoint inhibitors
Neutrophils found in the lung inhibit response to immune checkpoint inhibitors From Wiki Commons

In order to better understand these groups, the authors used an expression-profiling technology (Nanostring) and IHC to determine their gene and surface expression profiles. The Active group displayed a robust interferon-gamma (IFNg) signature that is associated with active T cells. Conversely, the Myeloid group did not display this activation signature. The Myeloid cases were associated with high expression of genes involved in neutrophil recruitment and function, as well as significantly increased expression of surface markers associated with neutrophils, but not other immune cell populations. In order to understand whether neutrophil content influenced patient outcome, the authors used clinical information for each case to classify patients into groups of complete response (CR), partial response (PR), stable disease (SD), or progressive disease (PD). Ratios of T cell content to neutrophil content within the tumor was significantly different in CR/PR groups compared to those with SD or PD, indicating that the relative abundance of neutrophils was associated with ICI treatment failure. When the authors calculated progression free survival time, the only group that displayed decreased time to progression were those with very low T cell/neutrophil ratios, identifying the subset of patients most likely to be unresponsive to ICI. Using a mouse model of lung cancer, the authors tested whether perturbing neutrophil numbers would lead to increased response to ICI. Only the combination of neutrophil blockade and ICI was successful at reducing lung tumor burden. While previous studies had identified that lack of T cells in the tumor environment was detrimental to patients, these studies identified that the relative numbers of T cells to neutrophils in the tumor environment can help predict response to ICI. Dr. Houghton explained: “As far as we know, this is the first time anybody has shown neutrophils contribute to treatment failure.” Additionally, Dr. Houghton’s group identified a potential solution to ICI treatment failure in NSCLC patients: treatment with neutrophil blocking agents. Combination treatment of these blocking agents with ICI treatment could be the next hope for NSCLC patients.

This work was supported by the National Institutes of Health, the Seattle Translational Tumor Research program, and the European Commission.

Fred Hutch/UW Cancer Consortium members Christina Balk, Robert H. Pierce, Mary W. Redman, and A. McGarry Houghton contributed to this work.

Julia Kargl, Xiaodong Zhu, Huajia Zhang, Grace H. Y. Yang, Travis J. Friesen, Melissa Shipley, Dean Y. Maeda, John A. Zebala, Jill McKay-Fleisch, Gavin Meredith, Afshin Mashadi-Hossein, Christina Baik, Robert H. Pierce, Mary W. Redman, Jeffrey C. Thompson, Steven M. Albelda, Hamid Bolouri, and A. McGarry Houghton. Neutrophil content predicts lymphocyte depletion and anti-PD1 treatment failure in NSCLC. JCI Insight. 2019;4(24):e130850.


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