Abstract 2691
Background
LAG-3, expressed on exhausted T cells, negatively regulates effector T-cell activation and may promote regulatory T-cell activity. MHC II, one of the ligands for LAG-3, is expressed by antigen-presenting cells and is heterogeneously upregulated on tumor cells in a variety of cancers. The LAG-3/MHC II interaction may activate LAG-3 and inhibit antitumor immunity. We performed digital spatial analysis to define the geographic association of LAG-3+ tumor-infiltrating lymphocytes (TILs) with individual MHC II+ and MHC II− tumor cells.
Methods
Bladder and gastric tumor samples (n = 20 each) of varying MHC II+ tumor expression (0–100%) were serially sectioned and stained by IHC for LAG-3, MHC II (human leukocyte antigen-DP, -DQ, and -DR), and Pan-cytokeratin. Slides were scanned via an Aperio AT2 scanner using a 20× objective and whole slide images were digitally aligned and analyzed via HALO software. LAG-3 engagement scores for the density of LAG-3+ TILs (LAG-3-D) and the proportion in close proximity (within 30 µm) to tumor cells (LAG-3-P) were computed for each sample using R software.
Results
MHC II was expressed by at least 1% of tumor cells in 55% of bladder and 70% of gastric samples. LAG-3-D and LAG-3-P within an individual tumor were significantly greater when associated with MHC II+ tumor cells (median [interquartile range] LAG-3-D = 6.53 [1.76, 24.9] cells/mm2; LAG-3-P = 46.7 [30.1, 70.4] % engaged) compared to MHC II− tumor cells (LAG-3-D = 0.616 [0.213, 2.38] cells/mm2 [P < 0.001]; LAG-3-P = 17.5 [6.09, 30.1] % engaged [P < 0.001]). Furthermore, we found significantly lower LAG-3/MHC II− tumor engagement by LAG-3-P in gastric compared to urothelial tumors (P < 0.001).
Conclusions
Digital spatial analysis of tumor cells and TILs in the tumor microenvironment is feasible without multiplex assays and can capture cell–cell relationships in tumors with heterogeneous MHC II staining. These data suggest preferential localization of LAG-3-expressing TILs to MHC II+ tumor cells within a proximity that may allow engagement and activation of LAG-3 and help define the importance of spatial analysis in predictive biomarker development for immunotherapy.
Clinical trial identification
Editorial acknowledgement
Editorial assistance was provided by Kathryn Woods, PhD, of Complete HealthVizion, funded by Bristol-Myers Squibb.
Legal entity responsible for the study
Bristol-Myers Squibb.
Funding
Bristol-Myers Squibb.
Disclosure
C.V. Hedvat: Shareholder / Stockholder / Stock options: Bristol-Myers Squibb; Full / Part-time employment: Bristol-Myers Squibb. G. Lee: Shareholder / Stockholder / Stock options: Bristol-Myers Squibb; Full / Part-time employment: Bristol-Myers Squibb. V. Baxi: Full / Part-time employment: Bristol-Myers Squibb. K. Dziuba: Full / Part-time employment: Bristol-Myers Squibb. D. Locke: Shareholder / Stockholder / Stock options: Bristol-Myers Squibb; Full / Part-time employment: Bristol-Myers Squibb. B. Li: Shareholder / Stockholder / Stock options: Bristol-Myers Squibb; Full / Part-time employment: Bristol-Myers Squibb. R. Edwards: Shareholder / Stockholder / Stock options: Bristol-Myers Squibb; Full / Part-time employment: Bristol-Myers Squibb.
Resources from the same session
2791 - Efficacy of weekly paclitaxel-bevacizumab combination in advanced non squamous non-small cell lung cancer (NSCLC) : a retrospective multicentric study.
Presenter: Geoffroy Bilger
Session: Poster Display session 1
Resources:
Abstract
2916 - Post progression survival for patients treated with docetaxel/nintedanib in the SENECA trial
Presenter: Enrica Capelletto
Session: Poster Display session 1
Resources:
Abstract
1427 - Final results of randomized phase II trial of metronomic vs weekly oral vinorelbine (OV) as first-line chemotherapy (CT) in advanced NSCLC patients unfit to platinum-based CT (P-CT): Tempo-Lung EudraCT Number: 2014-003859-61
Presenter: Dariusz Kowalski
Session: Poster Display session 1
Resources:
Abstract
3789 - Pioglitazone and clarithromycin combined with metronomic low-dose chemotherapy versus nivolumab in patients with advanced non–small-cell lung cancer treated in 2nd-line and beyond: Outcomes from a randomized phase II trial (ModuLung)
Presenter: Daniel Heudobler
Session: Poster Display session 1
Resources:
Abstract
1519 - Predicting Chemotherapy Toxicity in Elderly Patients with Advanced Non-small Cell Lung Cancer: A Prospective Multicenter Study of the National Hospital Organization in Japan
Presenter: Masaki Kanazu
Session: Poster Display session 1
Resources:
Abstract
1874 - A prospective phase II trial of carboplatin (CBDCA) and nab-paclitaxel (nabPTX) for advanced non-small cell lung cancer (NSCLC) with interstitial lung disease (ILD)
Presenter: Toshiyuki Harada
Session: Poster Display session 1
Resources:
Abstract
3819 - Weekly Epirubicin as palliative treatment in elderly patients with malignant pleural mesothelioma.
Presenter: Paola Candido
Session: Poster Display session 1
Resources:
Abstract
3390 - Survival Prolongation by Rationale INnovative Genomics (SPRING): An international WIN Consortium phase I study exploring safety and efficacy of avelumab, palbociclib, and axitinib in advanced non-small cell lung cancer (NSCLC) with integrated genomic and transcriptomic correlates.
Presenter: Benjamin Solomon
Session: Poster Display session 1
Resources:
Abstract
5069 - Preliminary results from phase 1b study of spartalizumab plus chemotherapy for advanced non-small cell lung cancer (NSCLC)
Presenter: Armando Santoro
Session: Poster Display session 1
Resources:
Abstract
2041 - Efficacy results of selective AXL inhibitor bemcentinib with pembrolizumab following chemo in patients with NSCLC
Presenter: Jose Trigo Perez
Session: Poster Display session 1
Resources:
Abstract