Multicellular Spatial Organization Determines Immunotherapy Response

In triple-negative breast cancer (TNBC), immunotherapy has demonstrated some benefit in patients, but reliable biomarkers to distinguish responders from nonresponders are lacking. Wang and colleagues sought to determine the relationship between multicellular spatial organization within the tumor microenvironment (TME) and immunotherapy response in tissue collected from patients with TNBC enrolled in the NeoTRIP trial, a randomized trial of neoadjuvant immunotherapy. Imaging mass cytometry, which is able to quantify the phenotype, activation state, and spatial location of cells in the tumor, was used across three time points, including baseline, on-treatment, and posttreatment, and showed that cell phenotype, activation state, and spatial location influence the effects of immune checkpoint blockade (ICB) and differ in sensitive versus resistant tumors. The proliferative fractions of CD8⁺TCF1⁺ T cells and MHCII⁺ epithelial (cancer) cells were found to be strong predictors of immunotherapy response, followed by CD8⁺ granzyme B (GZMB)⁺ T cells and CD20⁺ B-cell heterotypic interactions with cancer cells. Moreover, investigation into the modifications to cell–cell interaction and cell densities early on treatment demonstrated a greater infiltration of CD8⁺GZMB⁺ T cells and CD8⁺PD-1⁺ exhausted T cells in ICB responders, while nonresponders had increasing levels of CD15⁺ cancer cells. Additionally, evaluation of the cellular dynamics of neoadjuvant immunotherapy revealed conserved dynamics, with immune cells increasing on treatment and decreasing after treatment along with a reduction in cancer cells and an increase in stromal cells, but the degree of change differed, with the early increase in the immune cell fraction being greater in responders to immunotherapy. Furthermore, TME activation and tumor structure were found to play a major role in treatment response in patients who receive immunotherapy, and early on-treatment biopsies could improve predictive accuracy and guide adaptive treatment strategies. In summary, this study shows that ICB distinctively remodels tumor structure, with critical proliferative fractions and cell–cell interactions driving ICB response, and suggests that systematic mapping of the tumor ecosystem could enable the realization of precision immuno-oncology.

Wang XQ, Danenberg E, Huang CS, Egle D, Callari M, Bermejo B, et al. Spatial predictors of immunotherapy response in triple-negative breast cancer. Nature 2023;621:868–76.

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