GZMKhigh CD8+ T effector memory cells are associated with CD15high neutrophil abundance in early-stage colorectal tumors and predict poor clinical outcome.

ABSTRACT Tumor contexture has emerged as a major prognostic determinant and tumor infiltrating CD8 + T cells have been associated with a better prognosis in several solid tumors, including early-stage colorectal cancer (CRC). However, the tumor immune infiltrate is highly heterogeneous and understanding how the interplay between different immune cell compartments impacts on the clinical outcome is still in its infancy. Here, we describe in a prospective cohort a novel CD8 + T effector memory population, which is characterized by high levels of Granzyme K (GZMK high CD8 + T EM ) and is correlated with CD15 high tumor infiltrating neutrophils. We provide both in vitro and in vivo evidence of the role of stromal cell-derived factor 1 (CXCL12/SDF-1) in driving functional changes on neutrophils at the tumor site, promoting their retention and increasing the crosstalk with CD8 + T cells. Mechanistically, as a consequence of the interaction with neutrophils, CD8 + T cells are skewed towards a CD8 + T EM phenotype and produce high levels of GZMK, which in turn decreases E-cadherin pathway. The correlations of GZMK high CD8 + T EM and neutrophils with both tumor progression in mice and early relapse in CRC patients demonstrate the role of GZMK high CD8 + T EM in promoting malignancy. Indeed, a gene signature defining GZMK high CD8 + T EM was associated with worse prognosis on a larger independent cohort of CRC patients and a similar analysis was extended to lung cancer (TCGA). Overall, our results highlight the emergence of GZMK high CD8 + T EM in early-stage CRC tumors as a hallmark driven by the interaction with neutrophils, which could implement current patient stratification and be targeted by novel therapeutics.