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Diversity and heterogeneity of immune states in non-small cell lung cancer and small cell lung cancer.

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.

SUBMITTER: Rice SJ

PROVIDER: S-EPMC8638918 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Non-small cell lung cancer (NSCLC) is the leading cause of cancer-related death in the world. Immunological analysis of the tumor microenvironment (immunoscore) shows great promise for improved prognosis and prediction of response to immunotherapy. However, the exact immune cell composition in NSCLC remains unclear. Here, we used flow cytometry to characterize the immune infiltrate in NSCLC tumors, non-cancerous lung tissue, regional lymph node, and blood. The cellular identity of >95% of all CD45+ immune cells was determined. Thirteen distinct immune cell types were identified in NSCLC tumors. T cells dominated the lung cancer landscape (on average 47% of all CD45+ immune cells). CD4+ T cells were the most abundant T cell population (26%), closely followed by CD8+ T cells (22%). Double negative CD4-CD8- T cells represented a small fraction (1.4%). CD19+ B cells were the second most common immune cell type in NSCLC tumors (16%), and four different B cell sub-populations were identified. Macrophages and natural killer (NK) cells composed 4.7 and 4.5% of the immune cell infiltrate, respectively. Three types of dendritic cells (DCs) were identified (plasmacytoid DCs, CD1c+ DCs, and CD141+ DCs) which together represented 2.1% of all immune cells. Among granulocytes, neutrophils were frequent (8.6%) with a high patient-to-patient variability, while mast cells (1.4%), basophils (0.4%), and eosinophils (0.3%) were less common. Across the cohort of patients, only B cells showed a significantly higher representation in NSCLC tumors compared to the distal lung. In contrast, the percentages of macrophages and NK cells were lower in tumors than in non-cancerous lung tissue. Furthermore, the fraction of macrophages with high HLA-DR expression levels was higher in NSCLC tumors relative to distal lung tissue. To make the method readily accessible, antibody panels and flow cytometry gating strategy used to identify the various immune cells are described in detail. This work should represent a useful resource for the immunomonitoring of patients with NSCLC.

Project description:ObjectivePatient-derived xenograft (PDX) models have shown great promise in preclinical and translational applications, but their consistency with primary tumors in phenotypic, genetic, and pharmacodynamic heterogeneity has not been well-studied. This study aimed to establish a PDX repository for non-small cell lung cancer (NSCLC) and to further elucidate whether it could preserve the heterogeneity within and between tumors in patients.MethodsA total of 75 surgically resected NSCLC specimens were implanted into immunodeficient NOD/SCID mice. Based on the successful establishment of the NSCLC PDX model, we compared the expressions of vimentin, Ki67, EGFR, and PD-L1 proteins between cancer tissues and PDX models using hematoxylin and eosin staining and immunohistochemical staining. In addition, we detected whole gene expression profiling between primary tumors and PDX generations. We also performed whole exome sequencing (WES) analysis in 17 first generation xenografts to further assess whether PDXs retained the patient heterogeneities. Finally, paclitaxel, cisplatin, doxorubicin, atezolizumab, afatininb, and AZD4547 were used to evaluate the responses of PDX models to the standard-of-care agents.ResultsA large collection of serially transplantable PDX models for NSCLC were successfully developed. The histology and pathological immunohistochemistry of PDX xenografts were consistent with the patients' tumor samples. WES and RNA-seq further confirmed that PDX accurately replicated the molecular heterogeneities of primary tumors. Similar to clinical patients, PDX models responded differentially to the standard-of-care treatment, including chemo-, targeted- and immuno-therapeutics.ConclusionsOur established PDX models of NSCLC faithfully reproduced the molecular, histopathological, and therapeutic characteristics, as well as the corresponding tumor heterogeneities, which provides a clinically relevant platform for drug screening, biomarker discovery, and translational research.

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Diversity and heterogeneity of immune states in non-small cell lung cancer and small cell lung cancer.

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