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Y. Hayashi
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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 05.04 - Distinct Immunosuppressive Microenvironment Determines Poor Prognosis of Nonsmokers with Adenocarcinoma of Non-Small Cell Lung Cancer (ID 7388)
16:00 - 16:05 | Author(s): Y. Hayashi
- Abstract
- Presentation
Background:
Recent clinical trials have demonstrated the efficacy of immune checkpoint inhibitors in advanced non-small cell lung cancer (NSCLC). However, not all the patients receive survival benefit from these immunotherapies. In an attempt to refine the current strategy of cancer immunotherapy to treat NSCLC, we examined the influence of tumor-infiltrating lymphocytes (TILs) on postoperative survival.
Method:
We evaluated the prognostic significance of TILs (CD4[+], CD8[+], and FOXP3[+]) comprehensively by immunohistochemical (n = 234) and immune-related gene expression analysis (n = 58), and explored the relationship between immune features and clinical characteristics including histological types, smoking habit, epidermal growth factor receptor mutation, and postoperative survival.
Result:
Compared with non-adenocarcinoma (non-AD) patients, adenocarcinoma (AD) tumors had significantly higher number of tumor-infiltrating CD4[+] T cells (P < 0.05) but lower CD8[+] T cells and FOXP3[+] T cells (P < 0.01). We found higher accumulation of CD8[+] T cells in non-AD patients was correlated with longer survival, indicating it is a better prognostic factor (P < 0.02). On the contrary, high accumulation of CD8[+] T cells and FOXP3[+] T cells were identified as unfavorable prognostic factors (P < 0.05) in AD patients, particularly in AD nonsmokers (P < 0.02). The expression of activated T cell-related genes including interferon gamma and granzyme was associated with CD8[+] T-cell accumulation in non-AD patients, but not in AD patients, especially in AD nonsmokers. Infiltrating CD8[+] T cells were significantly less activated in immunosuppressive microenvironment with high expression of immunoregulation related genes including GATA3, IL13, CCR4 and CCL17 in AD nonsmokers (P < 0.05). In AD nonsmokers, there are possibly immunodysfunctional CD8[+] GATA3[+] T cells (P < 0.01) and immunoregulatory CD8[+] FOXP3[+] T cells (P < 0.01), accompanied by immunoregulatory CD4[+] FOXP3[+] CCR4[+] T cells (P < 0.01) that may be recruited by CCL17 produced by tumor-associated CD163[+] macrophages (P < 0.05) in IL13-associated tumor microenvironments (P < 0.05).
Conclusion:
In contrast to presence of activated CD8[+] T cells in non-AD, CD8[+] T cells are not activated, and may include dysfunctional and immunoregulatory T cells, accompanied by FOXP3[+] regulatory T cells and M2-like macrophages in IL13-associated tumor microenvironment of AD nonsmokers. Our study suggests that modulation of such immunosuppressive condition may be an attractive strategy for treatment of AD nonsmokers including immune-checkpoint blockade.
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P1.05 - Early Stage NSCLC (ID 691)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: Early Stage NSCLC
- Presentations: 1
- Moderators:
- Coordinates: 10/16/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)
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P1.05-009 - Analysis of Postoperative Prognosis in Terms of the Difference Between the Invasive Growth Area and the Total Tumor Diameter (ID 9888)
09:30 - 09:30 | Author(s): Y. Hayashi
- Abstract
Background:
In the 8[th] edition of the TNM classification of lung cancer, the T descriptor reflects the invasive growth area, which is not always equal to the total tumor diameter. In this study, we analyzed the difference in postoperative prognosis between tumors for which the invasive growth area was equal to the total tumor diameter and those for which the invasive growth area was smaller than the total tumor diameter.
Method:
One hundred forty-two patients with pathological stage I lung adenocarcinoma that was completely resected in our institute were enrolled. Adenocarcinoma in situ and minimally invasive adenocarcinoma were excluded. The average age at operation was 67.8±9.7 years, 87 patients were male, the average total tumor diameter was 1.9±0.6 cm, and the average invasive growth area was 1.6±0.6 cm. In 61 patients, the invasive growth area was smaller than the total tumor diameter (Group A), and in the remaining 81, the invasive growth area was equal to the total tumor diameter (Group B). The postoperative prognosis was compared between Groups A and B.
Result:
The estimated 5-year recurrence-free survival (RFS) probabilities by the Kaplan-Meier method in Groups A and B were 94.4% and 70.1%, respectively (p = 0.002, log-rank test). By a log-rank test, T factor (p < 0.001) and lymphatic permeation (p = 0.031) were also significantly associated with RFS. By a multivariate COX proportional hazards model, Group B (p = 0.045) and a pathological T descriptor of T1c or more (p = 0.001) were independently associated with RFS. Group B had a higher percentage of smokers (p = 0.004) and a higher percentage of cases in which the predominant histological subtype was other than a lepidic pattern (p < 0.001).
Conclusion:
Tumors for which the invasive growth area is equal to the total tumor diameter are associated with smoking and a predominant subtype of other than a lepidic pattern, and have a worse prognosis than tumors for which the invasive growth area is smaller than the total tumor diameter.
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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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P3.02-084 - FGF9-FGFR Pathway Induce Neuroendocrine Differentiation in Lung Epithelial Cells (ID 7553)
09:30 - 09:30 | Author(s): Y. Hayashi
- Abstract
Background:
Small cell lung cancer (SCLC), an aggressive and metastatic disease, accounts for about 15% of lung cancer. Neuroendocrine differentiation is essential molecular event in SCLC development. The mechanisms of neuroendocrine differentiation and SCLC development remain elusive. For the improvement of the prognosis of SCLC patients, clarification of the mechanisms of neuroendocrine differentiation is essential.
Method:
For in vitro experiments, a stable cell line with constitutive expression of FGF9 in MLE12 (a mouse lung alveolar type II cell line transformed by SV40 large T antigen) was established by retroviral infections (H69: SCLC cell line, MLE12: mouse lung epithelial cell line transformed by SV40). Using these cell lines, the effect of FGF9 on proliferation, colony formation capacity and downstream signaling was evaluated by MTS assay, softagar colony formation assay and Western blotting, respectively. For in vivo experiments, these cell lines were transplanted into the immunodeficient mice subcutaneously, and the size of tumor was measured. To evaluate the efficacy of FGFR inhibitors for FGF9-driven lung cancers, AZD4547, selective FGFR inhibitor, was orally administered. For pathological characterization of the tumors, immunohistochemicalstry staining was performed. For patients study, 31 SCLC samples were obtained and the expression of FGF9 was evaluated by immunohistochemistry.
Result:
FGF9 is highly expressed in human SCLC samples (80.6%).FGF9 has oncogenic ability in vitro and its effect may be exerted by the activation of MAPK pathway through FGFR1 and FGFR3 in MLE12 cells. Unexpectedly, pathological analysis revealed FGF9-driven tumors exhibited SCLC histology. FGF9 transforms lung alveolar type II cells to SCLC in vitro and in vivo. Selective FGFR inhibitor, AZD4547 suppressed tumor growth of FGF9-driven MLE12 tumors.
Conclusion:
These results suggest that FGF9 has roles of tumor initiation and progression in lung cancer, especially in SCLC. SCLC which highly expresses FGF9 might may be a target of FGFR inhibitors.
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P3.13 - Radiology/Staging/Screening (ID 729)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: Radiology/Staging/Screening
- Presentations: 1
- Moderators:
- Coordinates: 10/18/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)
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P3.13-031 - Predicting Factor for the Dissociation of the Diameter Between Radiographical Solid Part and Pathological Invasive Part in Lung Adenocarcinoma (ID 10184)
09:30 - 09:30 | Author(s): Y. Hayashi
- Abstract
Background:
In part-solid nodule of lung adenocarcinoma, the diameter of the solid part in computed tomography(CT) scan correlates with the diameter of the pathological invasive part. However, there are some cases revealing dissociation between them. We analyzed clinical factors predicting the dissociation of the diameter between radiographical solid part and pathological invasive part in adenocarcinoma less than 3 cm.
Method:
Among 291 cases with a lung adenocarcinoma smaller than 3 cm, we identified 91 cases whose solid part in preoperative thin-slice CT scan was less than 5 mm. Based on pathological diagnosis of invasive part, we divided these cases into Adenocarcinoma in situ/Minimally Invasive Adenocarcinoma(AIS/MIA) group (less than 5 mm) and Massive invasion group (5mm or larger), and retrospectively analyzed the clinicopathological factors. We also performed logistic regression analysis to detect the factors predicting the dissociation between radiographical and pathological findings.
Result:
Of 91 cases, 67 cases were in AIS/MIA group (AIS: 57, MIA: 10) and 24 cases were in Massive invasion group. In univariative analysis, cases of Massive invasion group were significantly higher in Brinkman index, CEA, age, and total tumor size than those of AIS/MIA group (p = 0.02, 0.01, 0.04, 0.03 respectively). With these detected four factors, we performed logistic regression analysis after determining threshold by ROC curve, which resulted in Brinkman index equal or larger than 400, and age equal or elder than 67 as significant predictive factors for Massive invasion group (p < 0.01, p = 0.05 respectively). Among 11 cases positive for these two factors, 7 cases (63.6 %) were in Massive invasion group.
Conclusion:
In the cases of radiographical AIS/MIA, the diameter of pathological invasive part tends to exceed 5 mm if Brinkman index equal or larger than 400, and age equal or elder than 67.
