Abstract 5667: Biomarkers associated with tertiary lymphoid structures are elevated in lung and bladder cancer patients who respond to durvalumab treatment
Authors: Sridhar Sriram , Morehouse Christopher M. , Shreshta Yashaswi , Rebelatto Marlon , Achour Ikbel , Kagiampakis Ioannis , Oflazoglu Ezogelin , Streicher Katie 
Published: September 2020

Introduction: Tertiary lymphoid structures are ectopic formations arising in areas of chronic inflammation, including cancers. TLS formation detected in tumors is thought to be associated with favorable prognosis, and markers of TLS formation and activity are currently being elucidated. The objective of this study was to determine the association between genes associated with TLS formation and outcomes in lung and bladder cancer patients treated with durvalumab (D).

Methods: Previously published TLS-associated genes and gene signatures (Fridman et al., 2019) were assessed in baseline tumor biopsy RNA sequencing data from D-treated (monotherapy) non-small cell lung (NSCLC, n = 97) and bladder (BLCA, n = 62) cancer patients from a nonrandomized phase Ib/II clinical trial (1108/NCT01693562), as well as in lung adenocarcinoma (LUAD, n = 594), squamous cell carcinoma (LUSC, n = 551) and bladder cancer (BLCA, n = 433) cohorts from TCGA. Kaplan-Meier analysis was performed to determine associations between TLS-related signature expression at baseline and overall survival (OS) in D-treated patients, as well as in LUAD, LUSC, and BLCA patients from TCGA to determine prognostic significance of these signatures. TLS-related signatures were also compared in D-treated responders and non-responders via ANOVA.

Results: Higher levels of CXCL13 transcript in D-treated patients was associated with better median OS (20.2 vs. 6.5 months in CXCL13-high vs. low patients respectively, p = 0.01). CXCL13 expression was not significantly associated with survival in either LUAD or LUSC TCGA patients. Elevated expression of TLS-related chemokine and T-follicular helper cell (Tfh) signatures were also linked to better OS in D-treated patients (p &lt; 0.05) compared to lung cancer patients in TCGA. These signatures were significantly elevated in D-treated responders compared to patients with progressive disease (fold-change &gt; 1.5, p &lt; 0.05). In D-treated BLCA patients, elevated chemokine and Tfh signatures were associated with better OS (median OS not reached in signature-high patients, p &lt; 0.05). Both signatures were not associated with OS in BLCA patients from TCGA. In BLCA D-treated complete responders (n = 4), all TLS-related markers were significantly elevated compared to patients with progressive disease. Elevated levels of CXCL13 transcript and either PDL1 protein or interferon-γ gene signature levels tracked with better OS in D-treated patients. Assessment of TLS structures via immunohistochemistry in the same patients is currently being explored.

Conclusions: TLS-related genes were elevated at baseline in D-treated NSCLC and BLCA patients with better response and OS. Modulation of these signatures was predictive of IO response, as they were not associated with survival in treatment naïve patients in TCGA. These results enhance understanding of mechanisms driving increased immunogenicity in IO-responsive patients.

Citation Format: Sriram Sridhar, Christopher M. Morehouse, Yashaswi Shreshta, Marlon Rebelatto, Ikbel Achour, Ioannis Kagiampakis, Ezogelin Oflazoglu, Katie Streicher. Biomarkers associated with tertiary lymphoid structures are elevated in lung and bladder cancer patients who respond to durvalumab treatment [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5667.