155P - The molecular basis of the lymphocyte stability index (LSI): A pan-cancer peripheral biomarker for survival post immune checkpoint blockade (ICB)

Background

Dynamic peripheral blood biomarkers for response to immune checkpoint blockade (ICB) are lacking. Lymphocyte count stability post-initiation of treatment (the ‘Lymphocyte Stability Index’, LSI) is significantly associated with progression-free and overall survival (OS) in metastatic melanoma (MM), as well as NSCLC and renal cell cancer. Notably, a single nucleotide polymorphism at rs16906115 (intronic to IL7) is associated with increased LSI, indicating non-tumour effects of systemic immunity. We sought to test the effect of treatment on LSI in MM and explore underlying molecular mechanisms.

Methods

Using treatment, blood count and survival data from 318 patients, we investigated the association between LSI and OS in MM, subdivided by treatment received and development of toxicity. We performed bulk (n=250) and single cell (n=18) RNA sequencing on peripheral blood from a cohort of patients with MM treated with ICB, correlating molecular findings with LSI.

Results

LSI was significantly associated with improved OS regardless of whether single agent PD-1, single-agent CTLA-4 or combination PD-1 and CTLA-4 blockade was received (HR 0.41, 0.23 and 0.34, respectively. All p<0.001), or whether toxicity developed. There was no difference in OS between patients with stable LSI, regardless of treatment received. CD8⁺ T cells from patients with high LSI had a unique gene expression profile, with a positive correlation between LSI and expression of gene sets relevant to anti-tumour immune responses. Conversely, patients with low LSI showed activation of Type I Interferon gene expression. Analysis of cellular dynamics within single cell data demonstrated unique innate-adaptive interactions via specific receptor-ligand pairs, suggesting potentiation of T cell responses by monocytic populations.

Conclusions

The LSI is a simple dynamic peripheral biomarker for survival following ICB treatment that reflects innate, primarily non-tumour factors. Activation of Type I interferons correlates with lymphocyte instability, providing a novel avenue for therapeutic intervention. Further, LSI may permit effective on-treatment stratification of immunotherapy.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

The authors.

Funding

The Wellcome Trust, CRIS Cancer Foundation, NIHR, Cancer Research UK.

Disclosure

All authors have declared no conflicts of interest.