Topography of cancer-associated immune cells in human solid tumors

Abstract

Lymphoid and myeloid cells are abundant in the tumor microenvironment, can be quantified by immunohistochemistry and shape the disease course of human solid tumors. Yet, there is no comprehensive understanding of spatial immune infiltration patterns (‘topography’) across cancer entities and across various immune cell types. In this study, we systematically measure the topography of multiple immune cell types in 965 histological tissue slides from N = 177 patients in a pan-cancer cohort. We provide a definition of inflamed (‘hot’), non-inflamed (‘cold’) and immune excluded patterns and investigate how these patterns differ between immune cell types and between cancer types. In an independent cohort of N = 287 colorectal cancer patients, we show that hot, cold and excluded topographies for effector lymphocytes (CD8) and tumor-associated macrophages (CD163) alone are not prognostic, but that a bivariate classification system can stratify patients. Our study adds evidence to consider immune topographies as biomarkers for patients with solid tumors.

Coordinated cellular neighborhoods orchestrate antitumoral immunity at the colorectal cancer invasive front

“…In the iTME, T cells and macrophages are among the most abundant immune cells and are closely related to clinical outcome (Fridman et al, 2012;Fridman et al, 2017;Kather et al, 2017;Kather et al, 2018). This was supported by analysis of our CRC cohort, which identified T cell-and macrophage-enriched CNs.…”

“…Naturally, the question arises as to how a tumor avoids immune action, such as by T cell exclusion (Joyce and Fearon, 2015) or the increased prevalence of certain cell types, including Tregs, macrophages and myeloidderived suppressor cells (Gajewski et al, 2013;Hanahan and Weinberg, 2011;Kumar et al, 2016;Munn and Bronte, 2016). Several recent studies have characterized tumor-immune phenotypes in detail, but how spatial organization and the associated crosstalk between iTME components determine the effectiveness of the antitumoral immune responses has not yet been determined (Kather et al, 2017;Kather et al, 2018;Newell and Becht, 2018).…”

Fractal dimension, occupancy and hotspot analyses of B cell spatial distribution predict clinical outcome in breast cancer

“…However, it is well known that the higher the density of TILs and leukocytes infiltrating into cancer cell islands, the better the prognosis. The "inflamed" tumors were associated with a better response to immunotherapy than the "noninflamed" and "immune-excluded" tumors (12,(30)(31)(32)(33). Similarly, we find that higher densities of B cells as well as CD8 + and CD3 + T cells (and Th cells and Tregs to a lesser extent) in the cancer cell islands are also correlated with improved prognosis (Fig.…”

“…Regional differences in selective pressures produce microhabitats resulting in phenotypic and genetic heterogeneity (8,9). Looking at cell densities averaged over the entire tissue overlooks the spatial heterogeneity in the distribution of TILs within the tumor which may be clinically important (10)(11)(12). Furthermore, spatial heterogeneity could skew the density measured in tissue microarrays (TMA) which only account for a small region within each tumorsuch samples may give a poor estimate of the overall cell density, depending on the location of each TMA sample within the tissue.…”

Computational pathology and the understanding of disease

“…This has wide applicability and clarifies the notion that computational pathology will affect everyone involved in tissue‐based diagnostics and/or research. This includes the whole spectrum of tissue analysis, from regular diagnosis based on H&E‐stained sections and immunohistochemistry , through individual research projects to clinical trials , where pathology review, for example, is increasingly performed on whole slide images.…”