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A.A. Davis
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MA 05 - Immuno-Oncology: Novel Biomarker Candidates (ID 658)
- Event: WCLC 2017
- Type: Mini Oral
- Track: Immunology and Immunotherapy
- Presentations: 1
- Moderators:Yoichi Nakanishi, P. Mitchell
- Coordinates: 10/16/2017, 15:45 - 17:30, Room 303 + 304
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MA 05.11 - Endothelial Adhesion Molecule Overexpression Correlates to Decreased CD8 T Cells and Increased B/Treg Cells in Lung Cancer (ID 8609)
16:55 - 17:00 | Author(s): A.A. Davis
- Abstract
- Presentation
Background:
Immunotherapy has become a promising recourse for lung cancer therapy. The endothelium separates circulating immune cells and the tumor microenvironment, and it is necessary for immune cells to penetrate this barrier to accost the tumor. This requires cell-matrix interactions via endothelial adhesion molecules(EAM) such as selectin and integrin. While it is expected that higher expression of EAM is linked to greater immune cell infiltration in general, little is known as to its actual effect on various types of immune cells in human lung cancer.
Method:
Based on the TCGA database, mRNA-seq values of genes related to the leukocyte recruitment cascade were analyzed in 504 patient samples with lung squamous cell carcinoma(SCC) and 522 patient samples with lung adenocarcinoma. The genes were divided into 3 sets: rolling, firm adhesion, and transmigration. Immune cell infiltration of each set was analyzed using Gene Set Enrichment Analysis(GSEA), and p values were derived from Fisher’s exact and Chi-squared tests.
Result:
In lung SCC, overexpression(z score>2.0) of the above genes was statistically significantly correlated with decreased infiltration of activated CD4/CD8 T cells, but increased infiltration of activated B/Treg cells (Figure1). Similar trend was also observed in lung adenocarcinoma. Macrophage, dendritic cells, and natural killer cells showed increased infiltration in the EAM overexpression groups of both SCC and adenocarcinoma. Overall survival showed no significant difference in all three EAM gene overexpression groups in both types of lung cancer.Figure 1
Conclusion:
We demonstrate for the first time that overexpression of EAM genes is linked to differential infiltration of various immune cells (including decreased CD4/CD8 T cells and increased activated B/Treg cells) in human lung cancer tissue. Recruitment of B/Treg cells by EAM may have an impact on inactivation of infiltrated T cells in the tumor microenvironment. This suggests that EAM status may serve as a predictive biomarker for T cell-mediated immunotherapy.
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OA 07 - Biomarker for Lung Cancer (ID 659)
- Event: WCLC 2017
- Type: Oral
- Track: Biology/Pathology
- Presentations: 1
- Moderators:Philip Christopher Mack, Shinichi Toyooka
- Coordinates: 10/16/2017, 15:45 - 17:30, Room 503
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OA 07.03 - Circulating Tumor DNA Mutant Allele Frequency and Tumor Burden as Biomarkers for Response to Immune Checkpoint Blockade (ID 9606)
16:05 - 16:15 | Author(s): A.A. Davis
- Abstract
- Presentation
Background:
Identifying biomarkers to select patients who respond to immune checkpoint blockade in non-small cell lung cancer (NSCLC) remains a challenge. Cell-free circulating tumor DNA (ctDNA) has emerged as a non-invasive, quantitative method of monitoring genomic alterations in the peripheral blood. We evaluated the clinical utility of ctDNA mutant allele frequency (MAF) and tumor burden based on imaging as biomarkers for response to immune checkpoint blockade in NSCLC.
Method:
From a cohort of 136 patients with ctDNA samples, 20 patients were retrospectively identified with ctDNA testing before initiation of anti-PD-1/PD-L1 treatment or within 90 days of therapy initiation. ctDNA testing was performed by Guardant360 (Guardant Health, Redwood City, CA). MAF of the dominant clone was identified quantitatively for each patient. In addition, baseline tumor burden was estimated using RECIST version 1.1. MAF and tumor burden were correlated with progression free survival (PFS) and overall survival (OS). Logistic regression of response rate (RR) and clinical benefit rate (CBR) was also performed.
Result:
Higher median ctDNA MAF was correlated with significantly shorter PFS and OS (hazard ratio (HR) 3.4, p=0.03 and HR 10.4, p=0.03, respectively) (Figure 1). There was no significant association between tumor burden estimation and PFS and OS. However, tumor burden was significantly correlated with MAF (r=0.58, p=0.007). MAF and tumor burden estimation did not correlate with RR or CBR in this small sample. Figure 1
Conclusion:
ctDNA MAF appears to be a promising, non-invasive, prognostic biomarker for response to immune checkpoint blockade in NSCLC with higher MAF associated with shorter PFS and OS. ctDNA MAF may also serve as a surrogate for tumor burden. Prospective studies with serial ctDNA sampling are necessary to further validate these findings.
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P1.07 - Immunology and Immunotherapy (ID 693)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: Immunology and Immunotherapy
- Presentations: 2
- Moderators:
- Coordinates: 10/16/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)
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P1.07-034 - Pretreatment Neutrophil & Platelet Count as a Predictor for Unfavorable Clinical Outcome in Non-Small Cell Lung Cancer (NSCLC) (ID 10250)
09:30 - 09:30 | Author(s): A.A. Davis
- Abstract
Background:
The importance of tumor immune microenvironment in disease outcomes has already been established. We can speculate that markers present in patients’ complete blood count (CBC) such as absolute neutrophil count (ANC), absolute lymphocyte count (ALC), and absolute monocyte count (AMC) could potentially help predict clinical benefit. In addition, given the recently discovered T cell inhibitory role of platelets, we hypothesized that increased platelet counts may lower the efficacy of T cell mediated immune checkpoint inhibitors. Here, we explored how well the information obtained from the simple non-invasive peripheral blood CBC can predict clinical outcome to immunotherapy in NSCLC.
Method:
ANC, ALC, AMC, neutrophil lymphocyte ratio (NLR) and platelet values were collected for twenty NSCLC patients at two times points; pretreatment (t1) & approximately 2-3 weeks after first treatment (t2). Response to immune checkpoint inhibitors based on RECIST criteria (response rate (RR) and clinical benefit rate (CBR)), progression-free survival (PFS) and overall survival (OS) were examined. Cox regression analyses were performed for baseline and delta (t2-t1) CBC values while controlling for various other clinical variables.
Result:
Baseline ANC and AMC were significantly associated with both worse PFS and OS, respectively (ANC; HR= 1.30, p=0.004 & HR= 1.31, p=0.020, AMC; HR= 13.75, p=0.030 & HR= 38.14, p=0.042). Platelets showed significance for only worse OS (HR= 4.45, p=0.036). Delta hematological profiles did not show any significant differences in clinical outcome. In multivariate analyses adjusting for clinical variables, ANC remained as an independent predictor of unfavorable PFS. None of the above variables examined were predictive of RR or CBR. Figure 1
Conclusion:
Elevated pretreatment ANC appears to strongly predict shorter PFS and OS in patients with NSCLC treated with immunotherapy. Pretreatment platelets greater than 400K was linked with poor survival outcome. Further studies with a larger cohort and serial CBC collection during treatment are warranted to validate this study.
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P1.07-043 - Barrier Molecule Overexpression is Associated with Increased CD8 T Cells and Decreased B/Treg Cells in Human Lung Cancer (ID 8617)
09:30 - 09:30 | Author(s): A.A. Davis
- Abstract
Background:
Immunotherapy is an encouraging therapeutic option for lung cancer therapy. For immune cells to interact with tumors, they must first traverse the cell junctions between neighboring cells. While it is expected that higher expression of barrier molecules is linked to lesser immune cell infiltration in general, little progress has been made in our understanding of how these barrier molecules mechanistically interact with immune cells in lung cancer.
Method:
Barrier molecule genes were divided into 3 types: tight junction, adherens junction, and desmosome. mRNA-seq values of each type were analyzed in 504 patient samples with lung squamous cell carcinoma(SCC) and 522 patient samples with lung adenocarcinoma from the TCGA database. Immune cell infiltration of each set was evaluated using Gene Set Enrichment Analysis(GSEA), and p values were analyzed from Chi-squared and Fisher’s exact tests.
Result:
In lung adenocarcinoma, overexpression(z-score>2.0) of desmosome genes significantly correlated with increased infiltration of activated CD4/CD8 T cells, and Th17 cells, but decreased infiltration of activated B cells, mast cells, macrophages, and regulatory T cells(Figure1). There was no significant difference in the immune cell landscape of groups overexpressing desmosome genes in lung SCC. In addition, there was no significant difference in groups overexpressing tight or adherens junction genes in both types of cancer. Overall survival also showed no significant difference in all 3 barrier molecular gene overexpression groups in both types of lung cancer.Figure 1
Conclusion:
Our study demonstrates that elevated barrier molecule(desmosome) gene expression is associated with increased infiltration of cytotoxic CD8 T cells and decreased infiltration of activated B/Treg cells in human lung adenocarcinoma. The inverse association between cytotoxic CD8 T cells and activated B/Treg cells aligns with previous reports of tumor-infiltrating B cells inhibiting T cells. Further investigation is required to understand the roles of barrier molecules and its immune modulatory effect in various types of cancers.
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P3.02 - Biology/Pathology (ID 620)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: Biology/Pathology
- Presentations: 1
- Moderators:
- Coordinates: 10/18/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)
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P3.02-013 - Prognostic Role of Circulating Tumor DNA (ctDNA) and Immune Cell Biomarkers in Non-Small Cell Lung Cancer (NSCLC) (ID 10358)
09:30 - 09:30 | Author(s): A.A. Davis
- Abstract
Background:
Peripheral blood biomarkers can provide valuable information in a relatively non-invasive manner. In solid tumors, it has been suggested that ctDNA mutant allele frequency (MAF) and immune cell counts from peripheral blood complete blood count (CBC) at baseline may be associated with survival outcome. Here, we investigated the role of ctDNA MAF and immune cells as prognostic biomarkers that may predict overall survival in patients with NSCLC.
Method:
A retrospective cohort of 128 patients with ctDNA sample testing performed by ctDNA NGS test (Guardant360) were selected. ctDNA MAF of the dominant clone was collected. CBC’s drawn within a 1-2 week window (baseline) of ctDNA were reported for absolute neutrophil count (ANC), absolute lymphocyte count (ALC), absolute monocyte count (AMC), neutrophil lymphocyte ratio (NLR) and platelet count. Platelets and MAF were analyzed by quartiles (lower 75% vs highest 25%). Survival analyses and Cox regression analyses were performed on these variables.
Result:
A significant association was found for ANC (hazard ratio (HR) = 1.17, p<0.001), AMC (HR=1.98, p=0.037), MAF (HR=2.53, p=0.005), NLR>5(HR=2.98, p<0.001), and platelet counts (HR=2.49, p=0.006) with overall survival (OS), but not ALC. In multivariate analyses adjusting for clinical variables including age, sex, smoking status, histology, disease stage, number of prior lines of treatment, prior radiation, history of other cancers and ALK/EGFR mutation status, ANC remained as an independent predictor of OS(HR= 1.19, p<0.001). Figure 1
Conclusion:
Higher ANC, AMC, NLR, platelet counts and MAF were associated with poor overall survival. Further studies are required to validate our findings in patients with NSCLC.
