# Spatial Proximity of Immune Cell Pairs to Cancer Cells in the Tumor Microenvironment as Biomarkers for Patient Stratification

## TL;DR

This study shows that the spatial positioning of immune cells near cancer cells can predict patient survival and treatment response better than traditional methods.

## Contribution

The study introduces a new metric, the relative distance (RD) score, to quantify immune cell proximity to cancer cells for improved patient stratification.

## Key findings

- RD-scores were more strongly associated with overall patient survival than standard immunological metrics.
- The RD-score comparing B cells to intermediate monocytes showed the most significant association with improved survival.
- Normalized RD-scores improved the distinction between treatment responders and non-responders in triple-negative breast cancer.

## Abstract

The tumor microenvironment (TME) is known to influence both disease progression and treatment outcomes in cancer. In this study, we analyzed high-dimensional imaging mass cytometry data from lung adenocarcinoma and triple-negative breast cancer to examine how the spatial positioning of immune cells relates to clinical outcomes. We developed a relative distance (RD) score that quantifies the proximity of immune cell pairs to cancer cells. This metric showed stronger associations with patient survival and treatment response than conventional features such as cell fraction or density. Our results suggest that spatial immune features may serve as robust biomarkers for patient stratification and personalized therapy.

Background/Objectives: The tumor microenvironment (TME) plays a critical role in cancer progression by shaping immune responses and influencing patient outcomes. We hypothesized that the relative proximity of specific immune cell pairs to cancer cells within the TME could help predict their pro- or anti-tumor functions and reflect clinically relevant immune dynamics. Methods: We analyzed imaging mass cytometry (IMC) data from lung adenocarcinoma (LUAD) and triple-negative breast cancer (TNBC) cohorts. For each immune cell pair, we calculated a relative distance (RD) score, which quantifies the spatial difference in proximity to cancer cells. We assessed the prognostic and predictive significance of these RD-scores by comparing them with conventional features such as cell fractions, densities, and individual cell distances. To account for variations in cell abundance, we also derived normalized RD-scores (NRD-scores). Results: RD-scores were more strongly associated with overall patient survival than standard immunological metrics. Among all immune cell pairs, the RD-score comparing the proximity of B cells to that of intermediate monocytes showed the most significant association with improved survival. In TNBC, RD-scores also improved the distinction between responders and non-responders to immunochemotherapy and chemotherapy. Normalized RD-scores reinforced these findings by minimizing the influence of cell density and further highlighting the importance of immune cell spatial relationships. Conclusions: RD-scores offer a spatially informed biomarker that outperforms traditional metrics in predicting survival and treatment response. This approach provides a new perspective on immune cell behavior in the TME and has potential utility in guiding personalized cancer therapies and patient stratification.