Immune Infiltrates Are Prognostic Factors in Localized Gastrointestinal Stromal Tumors

TLDR

Cancer immunosurveillance depends on effector/memory CD8⁺ T cells with a TH1 profile, while NK‑cell–mediated control of malignancies remains largely unproven, and imatinib prolongs gastrointestinal stromal tumor survival through both direct tumor inhibition and indirect stimulation of T and NK cells. The study investigated the prognostic value of tumor‑infiltrating lymphocytes expressing CD3, Foxp3, or NKp46 (NCR1) in a cohort of patients with localized GIST. The authors quantified the densities of CD3⁺, Foxp3⁺, and NKp46⁺ TIL in tumor samples to assess their prognostic significance. High densities of activated CD3⁺ TIL and NKp46⁺ NK cells independently predicted progression‑free survival, added prognostic value beyond the Miettinen score and KIT mutation status, and suggested that distinct T and NK cell subsets contribute separately to GIST immunosurveillance, supporting prospective validation of immune biomarkers.

Abstract

Cancer immunosurveillance relies on effector/memory tumor-infiltrating CD8(+) T cells with a T-helper cell 1 (TH1) profile. Evidence for a natural killer (NK) cell-based control of human malignancies is still largely missing. The KIT tyrosine kinase inhibitor imatinib mesylate markedly prolongs the survival of patients with gastrointestinal stromal tumors (GIST) by direct effects on tumor cells as well as by indirect immunostimulatory effects on T and NK cells. Here, we investigated the prognostic value of tumor-infiltrating lymphocytes (TIL) expressing CD3, Foxp3, or NKp46 (NCR1) in a cohort of patients with localized GIST. We found that CD3(+) TIL were highly activated in GIST and were especially enriched in areas of the tumor that conserve class I MHC expression despite imatinib mesylate treatment. High densities of CD3(+) TIL predicted progression-free survival (PFS) in multivariate analyses. Moreover, GIST were infiltrated by a homogeneous subset of cytokine-secreting CD56(bright) (NCAM1) NK cells that accumulated in tumor foci after imatinib mesylate treatment. The density of the NK infiltrate independently predicted PFS and added prognostic information to the Miettinen score, as well as to the KIT mutational status. NK and T lymphocytes preferentially distributed to distinct areas of tumor sections and probably contributed independently to GIST immunosurveillance. These findings encourage the prospective validation of immune biomarkers for optimal risk stratification of patients with GIST.