Abstract 1025: Clinical outcomes and differential tumor immune microenvironment in patients with small cell lung cancer and paraneoplastic syndromes
Authors: Iams Wade T. , Shiuan Eileen , Meador Catherine B. , Roth Marc , Bordeaux Jennifer , Vaupel Christine , Wang Lucy L. , Schneider Joseph T. , Warner Jeremy L. , Zhao Zhiguo , Lovly Christine M. 
Published: August 2018

Abstract
Background
Among patients with small cell lung cancer (SCLC), approximately 20% develop a paraneoplastic syndrome (PNS). Neurologic PNS are immune-mediated phenomena predicated on host recognition of an onconeural antigen, while endocrinologic PNS are attributed to ectopic tumor secretion of normal hormones. The presence of neurologic PNS improves prognosis and endocrinologic PNS worsens prognosis in patients with SCLC. We hypothesized that tumors from patients with neurologic PNS may have increased TILs and PD-1/PD-L1 expression compared to tumors from patients with endocrinologic PNS and this improved immune recognition accounts for prognostic differences.
Methods
We searched electronic medical record text stored in the Vanderbilt University Medical Center (VUMC) clinical data warehouse to identify SCLC patients with and without a PNS. We obtained clinical information through manual, retrospective chart review using an IRB-approved protocol. Overall survival (OS) and progression free survival (PFS) were compared using a log rank test. Archived formalin fixed, paraffin embedded samples were obtained from the Vanderbilt University Pathology Tissue Repository. We performed multiplexed fluorescence immunohistochemistry combined with automated quantitative analysis (AQUA® Technoloy; Navigate BioPharma Services, Inc.) to assess PD-1, PD-L1, CD4, and CD8 expression. A PD-1/PD-L1 interaction score was calculated by measuring the total area of PD-1 positive cells within the proximity of PD-L1 positive cells. This area was then divided by the total area of all non-tumor nucleated cells in the image and multiplied by a factor of 10,000. CD4, CD8, and PD-1/PD-L1 interaction scores were compared using a two sample t-test or Wilcoxon Rank Sum test.
Results
A total of 145 SCLC patients were identified, 55 with a PNS (25 neurologic and 30 endocrinologic) and 90 control patients. Patients with neurologic PNS exhibited significantly improved OS and PFS compared to patients with endocrinologic PNS and control patients (median OS 24mo, 95% CI 16.4mo-not reached (NR), vs 12mo, 95% CI 8.3mo-15.5mo, vs 13mo, 95% CI 12.2mo-16mo; median PFS 14mo, 95% CI 9.3mo-NR vs 6mo, 95% CI 4.6mo-9.5mo, vs 7mo, 95% CI 6.6mo-8.1mo, respectively). Tumors from patients with neurologic PNS (n=9) had statistically significantly higher PD-1/PD-L1 interaction scores (p=0.02), and increased CD4 (p=0.01) and CD8 (p=0.003) T cell infiltrates compared to tumors from patients with endocrinologic PNS (n=11).
Conclusion
Our study of tumor tissue from patients with SCLC and PNS demonstrated a statistically significant increase in immune modulation markers' expression in patients with neurologic PNS. Tumor immunomodulation may be the driver of the improved prognosis that has been observed in ours and other retrospective cohorts of patients with SCLC and neurologic PNS.
Citation Format: Wade T. Iams, Eileen Shiuan, Catherine B. Meador, Marc Roth, Jennifer Bordeaux, Christine Vaupel, Lucy L. Wang, Joseph T. Schneider, Jeremy L. Warner, Zhiguo Zhao, Christine M. Lovly. Clinical outcomes and differential tumor immune microenvironment in patients with small cell lung cancer and paraneoplastic syndromes [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1025.