Immune Infiltrates Are Prognostic Factors in Localized Gastrointestinal Stromal Tumors

Abstract

Cancer immunosurveillance relies on effector/memory tumor-infiltrating CD8þ T cells with a T-helper cell 1(T H 1) 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 þ 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 þ TIL predicted progression-free survival (PFS) in multivariate analyses. Moreover, GIST were infiltrated by a homogeneous subset of cytokinesecreting 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. Cancer Res; 73(12); 3499-510. Ó2013 AACR.

HSP90 Inhibition Enhances the Anti-Tumor Efficacy of Combination Chemo Immunotherapy Targeting DNA Repair Proteins

“…Our findings also support the ability of combined TMZ/ HSP90i + ACT-based therapy to promote enhanced infiltration of melanomas by Type-1 (Tbet + ) CD8 + T cells (including the ACT population of CSFE-labeled CD8 + T cells) in association with improved treatment outcome, and are consistent with several recent reports supporting higher numbers of CD8 + TIL as a predictive biomarker for patient benefit to immunotherapy [44][45][46][47]. However, as these CD8 + T effector TIL produce IFN-γ (based on ELISA results), which can promote upregulated expression of immune checkpoint molecules such as PD-L1 [46] and [48] in the TME.…”

NKp30 isoforms and NKp46 transcripts in metastatic melanoma patients: Unique NKp30 pattern in rare melanoma patients with favorable evolution

“…NKp30 transcript analyses of patients were compared with 106 ageand sex-matched HV, a control series included in previous studies performed in GIST patients. 12 The relative expression of the three distinct isoforms (NKp30A, NKp30B and NKp30C) was significantly lower in melanoma patients than in HV (Fig. 1A).…”

Innate immune signaling and regulation in cancer immunotherapy

“…In fact, tumor-infiltrating CD8 + T cells have been detected in subsets of patients with various cancers such as melanoma and carcinomas of the head and neck, breast, lung, prostate, bladder, kidney, colon, ovary, and esophagus [3]. Importantly, this T cell-inflamed phenotype correlates with positive treatment outcomes in these cancers and has been proposed as a prognostic biomarker [3][4][5][6][7][8][9][10]. For instance, the CD8 + T cell content in the core and invasive margin of colorectal tumors, a parameter termed "immunoscore", has been reported to be a better predictor of post-surgery disease-free and overall survival than the standard TNM staging [11,12].…”