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
2273 - High performance of serial tumor biopsies in first in human (FIH) phase I trials.
Presenter: Jun Sato
Session: Poster Display session 1
Resources:
Abstract
5933 - Response rates and lesion-level progression patterns of solid tumor patients in an academic phase 1 program: implications for tumor heterogeneity
Presenter: Christopher Chen
Session: Poster Display session 1
Resources:
Abstract
3569 - Clinical Benefit and Response Rate in Early Phase Clinical Trials: First Report from a Single-Institution Study
Presenter: Antonio Marra
Session: Poster Display session 1
Resources:
Abstract
4139 - Patient (pt) selection for immunotherapeutic early-phase clinical trials (ieCTs): a single Phase I Unit experience
Presenter: Matteo Simonelli
Session: Poster Display session 1
Resources:
Abstract
4451 - Improving patient selection for immuno-oncology phase 1 trials: an external validation of five prognostic scores at Claudius Regaud Institute of Toulouse, Oncopôle (IUCT-O).
Presenter: Ghassan Al Darazi
Session: Poster Display session 1
Resources:
Abstract
1696 - Demonstrating the Changing Trends in Phase 1 Clinical Trials
Presenter: Christina Guo
Session: Poster Display session 1
Resources:
Abstract
3202 - Participation of Women in phase 1 oncology clinical trials
Presenter: Laura Vidal
Session: Poster Display session 1
Resources:
Abstract
4518 - Predictors for early trial discontinuation of patients with cancer participating in phase I clinical trials
Presenter: Joeri Douma
Session: Poster Display session 1
Resources:
Abstract
4368 - Safety of Tumor Treating Fields delivery to the torso: Meta analysis from TTFields clinical trials
Presenter: Federica Grosso
Session: Poster Display session 1
Resources:
Abstract
4615 - Proteomic Profiling Identifies Molecular Basis of Adverse Event to BPM31510 Exposure: Rationale for Comprehensive Molecular Pharmacodynamics (PD) in Phase 1 Clinical Trial Design
Presenter: Vivek Subbiah
Session: Poster Display session 1
Resources:
Abstract