Non–small cell lung cancer (NSCLC) is a leading cause of cancer-related deaths. Immune checkpoint blockade has improved survival for many patients with NSCLC, but most fail to obtain long-term benefit. Understanding the factors leading to reduced immune surveillance in NSCLC is critical in improving patient outcomes. Here, we show that human NSCLC harbors large amounts of fibrosis that correlates with reduced T cell infiltration. In murine NSCLC models, the induction of fibrosis led to increased lung cancer progression, impaired T cell immune surveillance, and failure of immune checkpoint blockade efficacy. Associated with these changes, we observed that fibrosis leads to numerically and functionally impaired dendritic cells and altered macrophage phenotypes that likely contribute to immunosuppression. Within cancer-associated fibroblasts, distinct changes within the
Col13a1
-expressing population suggest that these cells produce chemokines to recruit macrophages and regulatory T cells while limiting recruitment of dendritic cells and T cells. Targeting fibrosis through transforming growth factor–β receptor signaling overcame the effects of fibrosis to enhance T cell responses and improved the efficacy of immune checkpoint blockade but only in the context of chemotherapy. Together, these data suggest that fibrosis in NSCLC leads to reduced immune surveillance and poor responsiveness to checkpoint blockade and highlight antifibrotic therapies as a candidate strategy to overcome immunotherapeutic resistance.
Introduction
The Sysmex XN‐10 automated hematology analyzer (Sysmex Corporation) is routinely used in hematology laboratories to perform complete blood cell count with differential (CBC w/ diff). The sensitivity of this system for blast detection is unclear, since many prior studies evaluating the blast flagging capabilities of Sysmex XN series used the white precursor cell (WPC) channel, which is not cleared for use in the United States.
Methods
We assessed the blast flagging capabilities of the Sysmex XN‐10 compared with CellaVision (a cell image analyzer)‐assisted visual hematology results. We evaluated the following flags: “blasts?/abnormal lymph?” and “immature granulocytes present” and compared differences in turnaround time between methods.
Results
We collected data on 2239 CBC w/ diff Sysmex automated analyzer differential and CellaVision‐assisted visual differential from the inpatient hematology‐oncology population of a tertiary care medical center. Solely analyzing the first CBC/diff from each unique patient, both flags had a combined sensitivity of 100%, specificity of 50.2%, PPV of 21.7%, and NPV of 100%. The mean turnaround time for the automated differential was 19.5 minutes (SD 35.9 minutes) compared with 66.4 minutes for the CellaVision‐assisted visual differential (SD 68.5 minutes; P < 0.001; Figure 1).
Conclusion
The Sysmex XN‐10 abnormal lymphocyte/blast and immature granulocytes flags had excellent sensitivity and acceptable specificity in detecting circulating blasts with shorter turnaround time than the CellaVision‐assisted visual differential. Our study suggests that automated differentials performed on Sysmex XN‐10 can replace visual differentials as a first‐line screening method for blast detection with improved turnaround time in hematology‐oncology populations.
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