NEW HAVEN, CT – In non-small cell lung cancer (NSCLC), there are limited predictive biomarkers for anticancer immunotherapy. Proposed as candidate biomarkers for immune checkpoint inhibitors (ICI) in patients with advanced NSCLC are tumor-infiltrating lymphocytes (TILs).
A new study in the Journal for ImmunoTherapy of Cancer described the composition and spatial distribution of major TIL subsets in NSCLC. It also demonstrated the following:
- the outcome effect of CD8+ T cells or the T cell receptor (TCR) fraction in patients with programmed death ligand-1 (PD-L1) expressing tumors,
- the contribution of T cell dysfunction markers and
- the clinical significance of spatial immune heterogeneity.
Lead researchers from Yale School of Medicine and colleagues from the Louis Stokes VAMC in Cleveland and other institutions said their efforts also establish “a novel multidimensional metric to study spatial immune heterogeneity with strong biomarker potential.”1
Essentially, according to the report, the study team found that “CD8+ TIL density and the TCR fraction measured by whole-exome DNA sequencing can stratify survival after ICI in patients with PD-L1 positive tumors and support their use as biomarkers. Our work also supports the incorporation of T cell LAG-3 and spatial immune heterogeneity as exploratory ICI biomarkers.”
Background information in the article noted that TILs reflect adaptive antitumor immune responses in cancer and are generally associated with a favorable prognosis. How those related to clinical benefit from immune checkpoint inhibitors was unknown, however.
Using a multi-institutional cohort of baseline tumor samples from 179 patients with NSCLC treated with ICI., researchers employed multiplexed quantitative immunofluorescence panels to determine the association of major TILs subpopulations, CD8+ cytotoxic T cells, CD4+ helper T cells and CD20+ B cells, and T cell exhaustion markers, programmed cell death protein-1 (PD-1),lymphocyte-activation gene 3 (LAG-3) and T cell immunoglobulin mucin-3 (TIM-3) with outcomes.
“TILs were preferentially located in the stromal tissue areas surrounding tumor-cell nests and CD8+ T cells were the most abundant subset. Higher density of stromal CD8+ cytotoxic T cells was significantly associated with longer survival, and this effect was more prominent in programmed death ligand-1 (PD-L1) positive cases,” the authors reported. “The role of baseline T cell infiltration to stratify PD-L1 expressing cases was confirmed by measuring the T cell receptor burden in an independent NSCLC cohort studied with whole-exome DNA sequencing. High levels of LAG-3 on T cells or elevated RQI heterogeneity index were associated with worse survival in the cohort.”
The authors concluded that baseline T cell density and T cell exhaustion marker expression can stratify outcomes in PD-L1 positive patients with NSCLC treated with ICI. “Spatial immune heterogeneity can be measured using the RQI and is associated with survival in NSCLC,” they added.
1. Lopez de Rodas M, Nagineni V, Ravi A, Datar IJ, Mino-Kenudson M, et. al.. J Immunother Cancer. 2022 Jun;10(6):e004440. doi: 10.1136/jitc-2021-004440. PMID: 35649657; PMCID: PMC9161072.
