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

Abstract

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.

The evolving landscape of predictive biomarkers in immuno‐oncology with a focus on spatial technologies

“…Enrichment of PD‐1 + CD4 + T cells only within a granulocyte CN had a positive correlation with survival in a high‐risk patient subset 84 . Worse outcomes were associated with the combination of tumor and immune CNs, fragmentation of T cell and macrophage CNs, and disruption of inter‐CN communication 82 …”

“…In patients who responded to pembrolizumab, the effector‐type cellular neighbourhoods (CNs), including a tumor/DC CN and a tumor/CD4 + T‐cell CN, were significantly increased, while in non‐responder an immunosuppressive‐type CN enriched in regulatory T cells was significantly increased following treatment. Schürch et al 82 . identified spatially nuanced interactions between components of the immune TME.…”

Single-cell genomics to understand disease pathogenesis

“…By analyzing the effect of the cellular neighborhood on the expression of receptors in splenic immune cells, they revealed the emergence of erythroblasts and disease-specific regulatory T cells and identified their interactions with dendritic cells. Schürch et al re-engineered the CODEX method to be compatible with formalin-fixed paraffin-embedded tissue, conducted simultaneous profiling using 56 protein markers in 140 tissue regions from 35 patients with advanced-stage colorectal cancer, and identified 9 conserved, distinct cellular neighborhoods, which are a collection of components characteristic of the immune tumor microenvironment in colorectal cancer [ 24 ]. Jackson et al used mass cytometry imaging analysis, which allows labeling of all target proteins with heavy-metal-conjugated antibodies and quantification by point-by-point ablation of the samples coupled to mass spectrometry, and simultaneously quantified 35 biomarkers in ~170,000 cells on tissue specimens from nearly 350 patients with breast cancer [ 25 ].…”

A quantitative analysis of the interplay of environment, neighborhood, and cell state in 3D spheroids

“…Assessments of spatial heterogeneity for several types of tumors have been performed based on protein and transcript measurements (Shah et al , 2017; Regev et al , 2017; Moffitt et al , 2018; Keren et al , 2018; Ali et al , 2020; Jackson et al , 2020; Schürch et al , 2020). Missing, however, is a quantitative understanding of how the tissue environment influences heterogeneity.…”