Coordinated Cellular Neighborhoods Orchestrate Antitumoral Immunity at the Colorectal Cancer Invasive Front

Summary

Antitumoral immunity requires organized, spatially nuanced interactions between components of the immune tumor microenvironment (iTME). Understanding this coordinated behavior in effective versus ineffective tumor control will advance immunotherapies. We re-engineered co-detection by indexing (CODEX) for paraffin-embedded tissue microarrays, enabling simultaneous profiling of 140 tissue regions from 35 advanced-stage colorectal cancer (CRC) patients with 56 protein markers. We identified nine conserved, distinct cellular neighborhoods (CNs)—a collection of components characteristic of the CRC iTME. Enrichment of PD-1 ⁺CD4 ⁺ T cells only within a granulocyte CN positively correlated with survival in a high-risk patient subset. Coupling of tumor and immune CNs, fragmentation of T cell and macrophage CNs, and disruption of inter-CN communication was associated with inferior outcomes. This study provides a framework for interrogating how complex biological processes, such as antitumoral immunity, occur through concerted actions of cells and spatial domains.

Graphical Abstract

Highlights

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  FFPE-CODEX multiplexed tissue imaging of 56 markers in 140 tissues of 35 CRC patients

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  Cellular neighborhoods reveal spatial organization of the tumor microenvironment

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  Altered organization of tumor and immune components in low- versus high-risk patients

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  Local enrichment of PD-1 ⁺CD4 ⁺ T cells correlates with survival in high-risk patients

Abstract

A multiplexed tissue imaging and computational analysis framework applied to colorectal cancer allows interrogation of how spatial organization of the immune tumor microenvironment is linked to clinical outcomes.