Abstract
Blood-based biomarkers including systemic inflammation (SI) indicators or circulating factors (cytokines, chemokines, or growth factors) are associated with a poor prognosis for lung cancer patients. Collectively these biomarkers can predict the immune state of a patient. We wanted to define and compare the immune states of small cell and non-small cell lung cancer patients, in the hopes that the information gained could lead to overall improvements in patient care and outcomes. Specimens and data from 235 patients was utilized, 49 surgically resected non-small cell lung cancer (NSCLC) patients with no evidence of disease (DF), 135 advanced non-small cell lung cancer (NSCLC), 51 small cell lung cancer (SCLC). SI markers neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte (PLR), systemic inflammation index (SII), and systemic inflammation response index (SIRI) were determined from blood counts. Forty-seven plasma cytokines were measured using a multiplex bead-based assay. Progression-free survival (PFS) and overall survival (OS) were assessed using Kaplan-Meier and Cox Proportional Hazards models. NSCLC patients had significantly high levels of SI markers than SCLC and DF patients, while NLR, PLR and SII were also higher in SCLC than DF patients. SI optimized marker values to differentiate SI value were; 6.04 (NLR), 320 (PLR), 1615 (SII), and 7.3 (SIRI). Elevated levels NLR (p<0.001), PLR (p<0.001), and SII (p = 0.018) were associated with a worse PFS and OS in NSCLC, while none of the markers were associated with PFS in SCLC patients. NSCLC patients with a poor outcome displayed heterogeneous immune states relative to systemic inflammation and circulating IL-6 markers. These groups could be distinguished based on the cytokines IL-8, TNFα, and IL-27. We identified heterogeneity of immune states in SCLC and NSCLC patients and in NSCLC patients with the poorest prognosis. This heterogeneity could be exploited to improve outcomes for these patients.
Highlights
non-small cell lung cancer (NSCLC) patients with advanced and metastatic disease with actionable mutations have derived clinical benefits from targeted agents, treatment options for NSCLC without actionable mutations and small cell lung cancer (SCLC) patients have been limited to chemotherapy, but modulation of the immune system with monoclonal antibodies acting as immune checkpoint inhibitors (ICI) has shown great potential for improving outcomes in these patients [2,3,4]
We explored the immune state of lung cancer patients by measuring four systemic inflammation (SI) markers and 47 plasma cytokines, chemokines, and growth factors in 235 patients to better understand how inflammation effects outcomes in lung cancer
The effect of the SI markers seen in these studies may include artifacts derived from an artificially low SI threshold value
Summary
NSCLC patients with advanced and metastatic disease with actionable mutations have derived clinical benefits from targeted agents, treatment options for NSCLC without actionable mutations and SCLC patients have been limited to chemotherapy, but modulation of the immune system with monoclonal antibodies acting as immune checkpoint inhibitors (ICI) has shown great potential for improving outcomes in these patients [2,3,4]. Durable responses in these patients can be achieved with ICI therapeutics. PD-L1 is a relatively poor marker for predicting activity of an ICI as it has limited sensitivity and specificity for identifying those patients most likely to respond
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