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
5444 - Analysis of the tumor microenvironment and tumor genotype through different stages of lung adenocarcinoma
Presenter: Peter Zink
Session: Poster Display session 1
Resources:
Abstract
3124 - Does Progress achieved in the Treatment of Patients with Metastatic Non-Small-Cell Lung Cancer (NSCLC) reach the Elderly Population?
Presenter: Jorune Suipyte
Session: Poster Display session 1
Resources:
Abstract
5142 - Prognostic factors for non-small cell lung cancer patients with driver mutation negative and brain metastases (HOT 1701)
Presenter: Yoshihito Ohhara
Session: Poster Display session 1
Resources:
Abstract
1580 - A novel risk classification system based on nomogram scores to predict survival of patients presenting with brain metastases at the first diagnosis of NSCLC
Presenter: Pengfei Cui
Session: Poster Display session 1
Resources:
Abstract
4442 - Comparison of real-world response rate (rwRR) to RECIST-based response rate in patients with advanced non-small cell lung cancer (aNSCLC)
Presenter: Xinran Ma
Session: Poster Display session 1
Resources:
Abstract
5405 - Estimating the cost and survival impact of new aNSCLC therapies in Canada with the iTEN model
Presenter: Parneet Kaur Cheema
Session: Poster Display session 1
Resources:
Abstract
1893 - SMARCA4 Deficient Non-Small Cell Lung Cancer (NSCLC): A Comprehensive Genomic Profiling (CGP) Study
Presenter: Stephen Graziano
Session: Poster Display session 1
Resources:
Abstract
5582 - Exploring Resistance to Nivolumab [NIV] applying an Immune Genomic Signature (IGS) in advanced pretreated NSCLC [PRINCiPe study]
Presenter: Sara Pilotto
Session: Poster Display session 1
Resources:
Abstract
1408 - DNA damage repair deficiency is associated with early resistance to crizotinib: whole-genome analysis in non-small cell lung cancer patients with ALK-fusion
Presenter: Dongyun He
Session: Poster Display session 1
Resources:
Abstract
5751 - Phase 3 ALTA-3 study of brigatinib (BRG) vs alectinib (ALC) in patients (pts) with advanced anaplastic lymphoma kinase (ALK)−positive non–small cell lung cancer (NSCLC) that progressed on crizotinib (CRZ)
Presenter: Sanjay Popat
Session: Poster Display session 1
Resources:
Abstract