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R.B. Cameron



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    P1.05 - Poster Session with Presenters Present (ID 457)

    • Event: WCLC 2016
    • Type: Poster Presenters Present
    • Track: Early Stage NSCLC
    • Presentations: 1
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      P1.05-003 - Coexpression of CD8a and PD-L1 Frequently Observed in Resected NSCLC Tumors from Smokers (ID 4764)

      14:30 - 15:45  |  Author(s): R.B. Cameron

      • Abstract

      Background:
      With the approval of anti-programmed cell death-1 (PD-1) therapy in advanced non-small cell lung cancer (NSCLC), identifying patients with early stage disease most likely to benefit from therapy has become a priority. It has been hypothesized that patients whose tumors show evidence of PD-1 mediated T cell exhaustion, via the presence of both tumor infiltrating lymphocytes (TILs) and PD-L1 expression, are more likely to respond to anti-PD-1 therapy (Teng et al, 2015). The current study utilized microarray analysis to evaluate the relationship between both clinicopathologic features and overall survival (OS) with tumor microenvironment (TME) composition.

      Methods:
      Gene expression microarray analysis was performed using the Agilent Whole Human Genome 4x44K 2-color platform for 319 NSCLC and 15 normal resection specimens. The reference sample was an equal mixture of 258 of the NSCLC samples. Rosetta Resolver and Statistica 13.0 were used for analysis. Samples with PD-L1 expression levels greater or unchanged from reference level were classified as positive, while those significantly lower [log (ratio)<0 and p<0.01] than the reference were classified as negative. CD8a expression was used as a surrogate for TILs as previously described by Ock et al. (2016), and categorized in the same manner as PD-L1. Relationships between TME composition and clinicopathologic features were evaluated with the chi-square test. Survival analysis was performed using the Kaplan-Meier method and compared using the log-rank test.

      Results:
      In the 319 NSCLC samples the incidence of a Type I TME (+CD8a/+PD-L1) was 45%, Type II TME (-CD8a/-PD-L1) 12%, Type III (-CD8a/+PD-L1) 25%, and Type IV (+CD8a/-PD-L1) 18%. When assessing for survival, patients with a PD-L1 negative/CD8a positive (Type IV) TME had improved OS compared to patients with PD-L1 negative/CD8a negative (Type II) TME (p=0.02). When assessed for smoking, ever smokers were more likely to evidence a PD-L1 positive/CD8a positive (type I) TME compared to never smokers, 49% vs 32%, while never smokers more frequently evidenced a PD-L1 positive/CD8a negative (Type III ) TME compared to ever smokers, 37% vs 22% (P=0.05). Interestingly, 75% of normal lung samples evidenced a PD-L1 positive/CD8a positive microenvironment.

      Conclusion:
      Evidence of both TILs and PD-L1 expression was observed in the majority of normal lung specimens and also more frequently in tumors from smokers compared to non-smokers. Patients whose tumors showed evidence of CD8a, but not PD-L1, had improved OS compared to patients without evidence of either. Future studies will utilize immunohistochemistry to corroborate these findings and investigate other components of the TME.

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    P2.01 - Poster Session with Presenters Present (ID 461)

    • Event: WCLC 2016
    • Type: Poster Presenters Present
    • Track: Biology/Pathology
    • Presentations: 1
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      P2.01-078 - Frequent High TIM-3 (HAVCR2) Expression in Resected NSCLC Specimens, Most Notably in Adenocarcinoma Histology (ID 5400)

      14:30 - 15:45  |  Author(s): R.B. Cameron

      • Abstract

      Background:
      Approved anti-programmed cell death-1 (PD-1) therapies have produced durable responses in advanced non-small cell lung cancer (NSCLC), but objective response rates in unselected populations remain modest at approximately 20%. As a result, therapies targeting other immune checkpoints are currently being investigated as monotherapy or in combination with anti-PD-1 therapy. One such immune checkpoint is T-cell immunoglobulin and mucin-domain containing 3 (TIM-3), which is involved in T-cell exhaustion and has also been found on NSCLC tumor cells, more frequently in adenocarcinoma. The present study sought to further characterize the expression of TIM-3 in resected NSCLC specimens via microarray analysis.

      Methods:
      Gene expression microarray analysis was performed using the Agilent Whole Human Genome 4x44K 2-color platform for 319 NSCLC and 15 normal lung resection specimens. The reference sample was an equal mixture of 258 of the NSCLC samples included in the study. Microarray data was imported into Rosetta Resolver for analysis. Samples with expression significantly greater than the reference level were classified as high, samples with expression unchanged from the reference were classified as moderate, and samples with significantly lower levels were classified as low (P<0.01). Relationships between TIM-3 expression and smoking status, histology, T stage, and gender were evaluated with the chi-square test. The three survival curves based on TIM-3 expression were compared and a single p-value based on chi-square test was determined using Statistica 13.0.

      Results:
      Within the 319 NSCLC tissue samples, 90 samples (28%) had high TIM-3 expression, 150 samples (47%) had moderate expression, and 79 samples (25%) had low expression. Interestingly, 47% (7/15) of normal lung samples evidenced high TIM-3 expression, while none had low TIM-3 expression. Tumors with adenocarcinoma histology had a greater percentage of samples with high TIM-3 expression, 34%, compared to those with squamous cell histology, 17% (p=0.03). Gender and T stage were not significantly related to TIM-3 expression level, while a trend towards high TIM-3 levels was observed in smokers compared to non-smokers (p=0.10). In this surgical cohort, TIM-3 expression did not appear to be prognostic for survival.

      Conclusion:
      Our findings suggest that high TIM-3 expression occurs frequently in resected NSCLC, supporting the ongoing evaluation of anti-TIM-3 therapy in NSCLC. Additionally, TIM-3 expression was more frequently high in adenocarcinoma, normal lung, and a trend towards high expression was noted in smokers. Future efforts will focus on identifying cell type specific TIM-3 expression via immunohistochemistry analysis and selecting patients for anti-TIM-3 clinical trials.