Studies Immune In fi ltrates Are Prognostic Factors in Localized Gastrointestinal Stromal Tumors

Cancer immunosurveillance relies on effector/memory tumor-infiltrating CD8þ T cells with a T-helper cell 1 (TH1) profile. Evidence for a natural killer (NK) cell-based control of humanmalignancies is still largelymissing. 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 CD3þ 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 CD3þ TIL predicted progression-free survival (PFS) in multivariate analyses. Moreover, GIST were infiltrated by a homogeneous subset of cytokinesecreting CD56 (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 KITmutational 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. 2013 AACR.

[1]  Aki Vehtari,et al.  Risk of recurrence of gastrointestinal stromal tumour after surgery: an analysis of pooled population-based cohorts. , 2012, The Lancet. Oncology.

[2]  C. Slingluff,et al.  Immunotype and immunohistologic characteristics of tumor-infiltrating immune cells are associated with clinical outcome in metastatic melanoma. , 2012, Cancer research.

[3]  R. Sciot,et al.  Mitotic Checkpoints and Chromosome Instability Are Strong Predictors of Clinical Outcome in Gastrointestinal Stromal Tumors , 2011, Clinical Cancer Research.

[4]  M. Heinrich,et al.  Gastrointestinal stromal tumours: origin and molecular oncology , 2011, Nature Reviews Cancer.

[5]  F. Bertucci,et al.  Human breast tumor cells induce self-tolerance mechanisms to avoid NKG2D-mediated and DNAM-mediated NK cell recognition. , 2011, Cancer research.

[6]  M. Pierotti,et al.  Proteomic detection of a large amount of SCGFα in the stroma of GISTs after imatinib therapy , 2011, Journal of Translational Medicine.

[7]  Eric C. Sorenson,et al.  Imatinib potentiates anti-tumor T cell responses in gastrointestinal stromal tumor through the inhibition of Ido , 2012 .

[8]  P. Validire,et al.  Profound coordinated alterations of intratumoral NK cell phenotype and function in lung carcinoma. , 2011, Cancer research.

[9]  L. Terracciano,et al.  Tumor infiltration by FcγRIII (CD16)+ myeloid cells is associated with improved survival in patients with colorectal carcinoma , 2011, International journal of cancer.

[10]  Jan Tavernier,et al.  Alternatively spliced NKp30 isoforms affect the prognosis of gastrointestinal stromal tumors , 2011, Nature Medicine.

[11]  M. Pierotti,et al.  Targeted therapy in GIST: in silico modeling for prediction of resistance , 2011, Nature Reviews Clinical Oncology.

[12]  M. Nykter,et al.  Integrative genomic characterization and a genomic staging system for gastrointestinal stromal tumors , 2011, Cancer.

[13]  C. Antonescu,et al.  Defects in succinate dehydrogenase in gastrointestinal stromal tumors lacking KIT and PDGFRA mutations , 2010, Proceedings of the National Academy of Sciences.

[14]  J. Blay,et al.  Discontinuation of imatinib in patients with advanced gastrointestinal stromal tumours after 3 years of treatment: an open-label multicentre randomised phase 3 trial. , 2010, The Lancet. Oncology.

[15]  B. Rubin,et al.  Kitlow stem cells cause resistance to Kit/platelet-derived growth factor alpha inhibitors in murine gastrointestinal stromal tumors. , 2010, Gastroenterology.

[16]  S. H. van der Burg,et al.  Anti‐inflammatory M2 type macrophages characterize metastasized and tyrosine kinase inhibitor‐treated gastrointestinal stromal tumors , 2010, International journal of cancer.

[17]  J. Blay,et al.  Validated prediction of clinical outcome in sarcomas and multiple types of cancer on the basis of a gene expression signature related to genome complexity , 2010, Nature Medicine.

[18]  A. Daneri-Navarro,et al.  Low NKp30, NKp46 and NKG2D expression and reduced cytotoxic activity on NK cells in cervical cancer and precursor lesions , 2009, BMC Cancer.

[19]  J. Blay,et al.  Cell Cycle/Apoptosis Molecule Expression Correlates with Imatinib Response in Patients with Advanced Gastrointestinal Stromal Tumors , 2009, Clinical Cancer Research.

[20]  J. Blay,et al.  Natural killer cell IFN-gamma levels predict long-term survival with imatinib mesylate therapy in gastrointestinal stromal tumor-bearing patients. , 2009, Cancer research.

[21]  C. Antonescu,et al.  Adjuvant imatinib mesylate after resection of localised, primary gastrointestinal stromal tumour: a randomised, double-blind, placebo-controlled trial , 2009, The Lancet.

[22]  F. Haller,et al.  Immune cells in primary gastrointestinal stromal tumors , 2008, European journal of gastroenterology & hepatology.

[23]  G. Altavilla,et al.  Natural killer cells infiltrating human nonsmall‐cell lung cancer are enriched in CD56brightCD16− cells and display an impaired capability to kill tumor cells , 2008, Cancer.

[24]  P. Dubreuil,et al.  The tyrosine kinase FES is an essential effector of KITD816V proliferation signal. , 2007, Blood.

[25]  Masahiro Takada,et al.  Role of natural killer cells in hormone-independent rapid tumor formation and spontaneous metastasis of breast cancer cells in vivo , 2007, Breast Cancer Research and Treatment.

[26]  H. Joensuu,et al.  Gastrointestinal stromal tumors with KIT exon 11 deletions are associated with poor prognosis. , 2006, Gastroenterology.

[27]  P. Nelson,et al.  Cytotoxic Markers and Frequency Predict Functional Capacity of Natural Killer Cells Infiltrating Renal Cell Carcinoma , 2006, Clinical Cancer Research.

[28]  P. Opolon,et al.  NK Cells Infiltrating a MHC Class I-Deficient Lung Adenocarcinoma Display Impaired Cytotoxic Activity toward Autologous Tumor Cells Associated with Altered NK Cell-Triggering Receptors1 , 2005, The Journal of Immunology.

[29]  J. Blay,et al.  CD4+CD25+ regulatory T cells inhibit natural killer cell functions in a transforming growth factor–β–dependent manner , 2005, The Journal of experimental medicine.

[30]  Y. Oda,et al.  Prognostic significance of expressions of cell-cycle regulatory proteins in gastrointestinal stromal tumor and the relevance of the risk grade. , 2005, Human pathology.

[31]  B. Nilsson,et al.  Gastrointestinal stromal tumors: The incidence, prevalence, clinical course, and prognostication in the preimatinib mesylate era , 2005, Cancer.

[32]  L. Sobin,et al.  Gastrointestinal Stromal Tumors of the Stomach: A Clinicopathologic, Immunohistochemical, and Molecular Genetic Study of 1765 Cases With Long-term Follow-up , 2005, The American journal of surgical pathology.

[33]  J. Blay,et al.  Novel mode of action of c-kit tyrosine kinase inhibitors leading to NK cell-dependent antitumor effects. , 2004, The Journal of clinical investigation.

[34]  K. Wilson,et al.  Structural Basis for the Autoinhibition and STI-571 Inhibition of c-Kit Tyrosine Kinase* , 2004, Journal of Biological Chemistry.

[35]  L. Larocca,et al.  Role of p16/INK4a in gastrointestinal stromal tumor progression. , 2004, American journal of clinical pathology.

[36]  Benoît Plancoulaine,et al.  A simple way of quantifying immunostained cell nuclei on the whole histologic section , 2003, Cytometry. Part A : the journal of the International Society for Analytical Cytology.

[37]  Samuel Singer,et al.  PDGFRA Activating Mutations in Gastrointestinal Stromal Tumors , 2003, Science.

[38]  G. Demetri,et al.  Clinical management of gastrointestinal stromal tumors: before and after STI-571. , 2002, Human pathology.

[39]  S. Lowe,et al.  Dissecting p53 tumor suppressor functions in vivo. , 2002, Cancer cell.

[40]  T. Jacks,et al.  STI571 inactivation of the gastrointestinal stromal tumor c-KIT oncoprotein: biological and clinical implications , 2001, Oncogene.

[41]  D. Tuveson,et al.  Effect of the tyrosine kinase inhibitor STI571 in a patient with a metastatic gastrointestinal stromal tumor. , 2001, The New England journal of medicine.

[42]  H. Anazawa,et al.  Stem cell growth factor: in situ hybridization analysis on the gene expression, molecular characterization and in vitro proliferative activity of a recombinant preparation on primitive hematopoietic progenitor cells. , 2001, The hematology journal : the official journal of the European Haematology Association.

[43]  K. Nakachi,et al.  Natural cytotoxic activity of peripheral-blood lymphocytes and cancer incidence: an 11-year follow-up study of a general population , 2000, The Lancet.

[44]  S. Hirota,et al.  Gain-of-function mutations of c-kit in human gastrointestinal stromal tumors. , 1998, Science.