GZMK^high CD8⁺ T effector memory cells are associated with CD15^high neutrophil abundance in early-stage colorectal tumors and predict poor clinical outcome

Abstract

Tumor contexture has emerged as a major determinant to establish prognosis and guide novel therapies 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 (GZMKhigh CD8+ TEM) and correlated with CD15high 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 crosstalk with CD8+ T cells. Mechanistically, as a consequence of the interaction with neutrophils, CD8+ T cells are skewed towards a CD8+ TEM phenotype, producing high levels of GZMK, which in turn decreased E-cadherin pathway. The correlation of GZMKhigh CD8+ TEM and neutrophils with both tumor progression in mice and early relapse in CRC patients demonstrate the role of GZMKhigh CD8+ TEM in promoting malignancy. Indeed, a gene signature defining GZMKhigh CD8+ TEM 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 GZMKhigh CD8+ TEM 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.

A novel stratification framework based on anoikis-related genes for predicting the prognosis in patients with osteosarcoma

“…CXCL12 is an important chemokine in T and NK cells that helps macrophages polarize into tumor-associated macrophages (51, 52). In addition, CXCL12 mediates the progression of rectal cancer by promoting the retention of neutrophils in tumors and increasing their interactions with CD8+ T cells (53). These findings not only suggest that lowlevel infiltration of immune cells in OS high-risk samples may be associated with poor prognosis but also highlight the non-negligible role of BNIP3 and CXCL12 in the regulation of immune cell biological behavior.…”

Multimodal single-cell profiling of intrahepatic cholangiocarcinoma defines hyperactivated Tregs as a potential therapeutic target

“…Compensation was performed by FlowJo by using BD Compbeads incubated with single antibodies, as previously described [49]. The cohorts of NSCLC, BC and CRC patients used to assess CD39 expression by tumor-infiltrating CD8+ T cells were previously described [28,32,50].…”