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Charles Caldwell Jr
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MA11 - Biomarkers of IO Response (ID 912)
- Event: WCLC 2018
- Type: Mini Oral Abstract Session
- Track: Immunooncology
- Presentations: 1
- Moderators:
- Coordinates: 9/25/2018, 10:30 - 12:00, Room 203 BD
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MA11.05 - Indoleamine 2,3-Dioxygenase Expression in Non-Small-Cell Lung Cancer: Analyses of Prevalence, Clinical Correlations and Prognostic Impact (ID 13309)
11:00 - 11:05 | Author(s): Charles Caldwell Jr
- Abstract
- Presentation
Background
Indoleamine 2,3-dioxygenase-1 (IDO-1) is a cytosolic enzyme involved in the catabolism of tryptophan; IDO-1-related immune suppression is due to decreased tryptophan availability and to the generation of tryptophan metabolites, culminating in substantial suppression of T-lymphocytes. Here we investigate IDO-1 expression in a cohort of non-small-cell lung cancer (NSCLC) specimens, both in tumor cells and in immune infiltrate, with correlation of IDO-1 to PD-L1 expression, clinical patient demographics and outcomes.
a9ded1e5ce5d75814730bb4caaf49419 Method
A cohort of 1.200 NSCLC samples were obtained from 437 patients who underwent surgical lung resections at Austin Health, Melbourne, Australia. IDO-1 expression was evaluated by immunohistochemistry. Correlations were assessed using Spearman and Kendall tests. A Cox proportional hazards (PH) model was used to assess if overall survival (OS) was associated with IDO-1 positivity in univariate and multivariable settings.
4c3880bb027f159e801041b1021e88e8 Result
Samples from 437 patients were analyzed for IDO-1 expression, with 111 (25.4%) determined as positive (H-Score ≥ 1) and 326 patients (74.6%) as negative (H-Score: 0). IDO-1 expression was determined to be greater in tumor immune infiltrate, with 406 patients (93.8%) determined as positive, while just 27 (6.2%) were IDO-1 negative. There was a significant positive correlation between IDO-1 positive tumor cells and immune cells (0.2167, p < 0.001). Both continuous and binary versions of tumor H-Score showed a significant positive correlation with the amount of tumor immune infiltrate (0.1806 and 0.1698, p < 0.0001, respectively). None of the analyzed variables (age, sex, histology, stage, EGFR, KRAS and PD-L1 status) were found to display a significant correlation with IDO-1 positivity in tumor and immune cells. IDO-1 positivity in tumor cells was found to be significantly associated with OS in the univariate setting and in the multivariable model where variables age, sex, histology, stage, EGFR, KRAS and PD-L1 status were included [P-value = 0.009 and 0.021, respectively; HR: 0.72 (95% CI: 0.55-0.95)]. IDO-1 positivity in immune cells was found to be significantly associated with OS in the univariate setting and was borderline significant in the multivariable model [P-value = 0.006 and 0.053, respectively; HR: 0.798 (95% CI: 0.635-1.003)].
8eea62084ca7e541d918e823422bd82e Conclusion
To our knowledge, this is the most extensive analysis of IDO-1 expression in NSCLC patients reported in the literature. Our results suggest the possible prognostic role of IDO-1 expression in tumor and immune cells, highlighting the relevance of IDO-1 detection in tumor tissue. Since new compounds targeting IDO-1 are actually under investigation, the identification of potential prognostic and predictive biomarkers will be needed.
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P2.04 - Immunooncology (Not CME Accredited Session) (ID 953)
- Event: WCLC 2018
- Type: Poster Viewing in the Exhibit Hall
- Track:
- Presentations: 1
- Moderators:
- Coordinates: 9/25/2018, 16:45 - 18:00, Exhibit Hall
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P2.04-13 - The Immune Checkpoint, HVEM Contribute to Immune Escape in Non Small Cell Lung Cancer of Lacking PDL1 Expression (ID 13116)
16:45 - 18:00 | Author(s): Charles Caldwell Jr
- Abstract
Background
Herpes Virus Entry Mediator (HVEM) is an important immune checkpoint in cancer recognition. HVEM expressed on tumor cell membranes activates immune cell signaling pathways leading to either inhibition of activity (BTLA) or activation of immune activity (LIGHT). The aim of this study is to investigate the prevalence of HVEM expression and its association with PDL1 expression in NSCLC.
a9ded1e5ce5d75814730bb4caaf49419 Method
A TMA of 527 resected NSCLC samples and 53 NSCLC cell lines were evaluated for HVEM and PD-L1 expression. The IHC assay for HVEM was optimized on the Dako Link48 autostainer using a polyclonal antibody from R&D Systems（AF356). PD-L1 IHC was performed on the Dako Link48 autostainer using the PD-L1 22C3 pharmDx kit. Scoring HVEM employed the H-score system while for PD-L1 the tumor proportion score (TPS) was used.
4c3880bb027f159e801041b1021e88e8 Result
HVEM expression in the NSCLC resected samples and cell lines revealed a positive H-score more than 1 was18.6%(77/415) and 45.3%(24/53) respectively. HVEM expression was significantly higher in patients with lymph node N2 metastasis (25.5% vs 7.9% vs 17.5%, P=0.046) when comparing with N1 or no lymph node metastasis, and was marginally significantly higher in patients with stage III/IV disease (24.5% vs 16.4%, P=0.059). Subgroup analysis showed that HVEM (median 45 vs 36 months, p=0.706) and PD-L1 expression (median 45 vs 48 months, p=0.178) status was not predictive of overall survival. HVEM was found to have a significant negative correlation with PD-L1 expression (r=-0.232, p=0.002, Figure 1A) in patients with NSCLC and also have a negative correlation in NSCLC cell lines(r=-0.055, p=0.764,Figure 1B).
8eea62084ca7e541d918e823422bd82e Conclusion
HVEM was found to be overexpressed in patients of NSCLC with advanced disease or lymph node metastasis and has a negative co-relationship with PD-L1 expression, while, it did not have a prognostic role in patients with NSCLC.
6f8b794f3246b0c1e1780bb4d4d5dc53
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P3.12 - Small Cell Lung Cancer/NET (Not CME Accredited Session) (ID 978)
- Event: WCLC 2018
- Type: Poster Viewing in the Exhibit Hall
- Track:
- Presentations: 1
- Moderators:
- Coordinates: 9/26/2018, 12:00 - 13:30, Exhibit Hall
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P3.12-13 - Expression of the Immune Checkpoint Axis-PVR/TIGIT in Small Cell Lung Cancer (ID 13994)
12:00 - 13:30 | Author(s): Charles Caldwell Jr
- Abstract
Background
The poliovirus receptor (PVR) is an immune checkpoint protein expressed on tumor cells. It has been reported to mediate activation of T cells via CD226 or inhibition through binding to T-cell Ig and ITIM domain (TIGIT). TIGIT competes with CD226 for binding to PVR, and exhibits stronger affinity for PVR. Recently we have found that PVR is highly expressed in SCLC cell lines. Characterizing the expression and significance of the PVR-TIGIT axis in SCLC will help us to better understand the immunology of SCLC and may lead to novel therapeutic strategies to combine checkpoint blocking agents for improved SCLC immunotherapy.
a9ded1e5ce5d75814730bb4caaf49419 Method
Immunohistochemistry (IHC) was performed to evaluate PVR protein expression in a TMA of 39 SCLC cell lines and a cohort TMA of 77 limited stage SCLC patients with clinical data. We analyzed both PVR and TIGIT in an independent cohort of 27 resected, limited-stage SCLC tumors.
4c3880bb027f159e801041b1021e88e8 Result
Thirty-seven cell lines (95%, 37/39) demonstrated staining for PVR and of those, 4 cell lines (10.3%, 4/39) showed strong staining (H-score ≥ 270). In the 77 SCLC patients cohort, PVR expressed predominantly in the membrane of tumor cells, with minimal expression observed on immune cells. PVR expression in the SCLC patient cohort was 82% with an arbitrary H-score cut-off of ≥ 50. Higher PVR expression was found for male patients (P=0.040). The expression of PVR increased with the tumor progressing from stage I to stage III (p =0.007). SCLC patients who had higher PVR expression demonstrated poorer prognosis and the difference was near statistically significant (p=0.050). Using the same cut-off (H-score ≥ 50) in the independent SCLC cohort, the prevalence of high PVR expression was 89% (24/27).
In the independent SCLC cohort, TIGIT was found to be expressed membranous or cytoplasm on the immune cells with weak to moderate staining. Immune cells with TIGIT staining were typically seen as variable size and aggregated toward the periphery of the tumor nest. TIGIT protein staining was demonstrated in 20 cases (74%). No association was found between PVR H-score and TIGIT expression by Fisher’s test (p=0.093).
8eea62084ca7e541d918e823422bd82e Conclusion
PVR is broadly expressed in SCLC cell lines and tumor tissues. The expression of TIGIT protein was also found in SCLC patients with weak to moderate staining. Blockade of the PVR-TIGIT pathway may represent a possible future target to immunotherapy in SCLC patients.
6f8b794f3246b0c1e1780bb4d4d5dc53
