Long-term Survival and Clinical Benefit from Adoptive T-cell Transfer in Stage IV Melanoma Patients Is Determined by a Four-Parameter Tumor Immune Signature

Four parameters were identified—CD8+ TILs, galectin-3+ tumors, galectin-9+ DCs, and a high M1/M2 ratio—whose combined presence was prognostic for long-term survival and predictive for sustained clinical benefit from adoptive T cell transfer in stage IV melanoma. The presence of tumor-infiltrating immune cells is associated with longer survival and a better response to immunotherapy in early-stage melanoma, but a comprehensive study of the in situ immune microenvironment in stage IV melanoma has not been performed. We investigated the combined influence of a series of immune factors on survival and response to adoptive cell transfer (ACT) in stage IV melanoma patients. Metastases of 73 stage IV melanoma patients, 17 of which were treated with ACT, were studied with respect to the number and functional phenotype of lymphocytes and myeloid cells as well as for expression of galectins-1, -3, and -9. Single factors associated with better survival were identified using Kaplan–Meier curves and multivariate Cox regression analyses, and those factors were used for interaction analyses. The results were validated using The Cancer Genome Atlas database. We identified four parameters that were associated with a better survival: CD8+ T cells, galectin-9+ dendritic cells (DC)/DC-like macrophages, a high M1/M2 macrophage ratio, and the expression of galectin-3 by tumor cells. The presence of at least three of these parameters formed an independent positive prognostic factor for long-term survival. Patients displaying this four-parameter signature were found exclusively among patients responding to ACT and were the ones with sustained clinical benefit. Cancer Immunol Res; 5(2); 170–9. ©2017 AACR.

[1]  J. Schachter,et al.  Predictors of tumor-infiltrating lymphocyte efficacy in melanoma. , 2016, Immunotherapy.

[2]  A. Ladányi,et al.  Prognostic and predictive significance of immune cells infiltrating cutaneous melanoma , 2015, Pigment cell & melanoma research.

[3]  R. Wirtz,et al.  Comparison of immunoreactive score, HER2/neu score and H score for the immunohistochemical evaluation of somatostatin receptors in bronchopulmonary neuroendocrine neoplasms , 2015, Histopathology.

[4]  Steven J. M. Jones,et al.  Genomic Classification of Cutaneous Melanoma , 2015, Cell.

[5]  C. Meyer,et al.  Ipilimumab-dependent cell-mediated cytotoxicity of regulatory T cells ex vivo by nonclassical monocytes in melanoma patients , 2015, Proceedings of the National Academy of Sciences.

[6]  D. Rimm,et al.  Characterization of PD-L1 Expression and Associated T-cell Infiltrates in Metastatic Melanoma Samples from Variable Anatomic Sites , 2015, Clinical Cancer Research.

[7]  E. Jaffee,et al.  Galectin-3 Shapes Antitumor Immune Responses by Suppressing CD8+ T Cells via LAG-3 and Inhibiting Expansion of Plasmacytoid Dendritic Cells , 2015, Cancer Immunology Research.

[8]  S. H. van der Burg,et al.  Expression of coinhibitory receptors on T cells in the microenvironment of usual vulvar intraepithelial neoplasia is related to proinflammatory effector T cells and an increased recurrence‐free survival , 2015, International journal of cancer.

[9]  S. H. van der Burg,et al.  Intraepithelial macrophage infiltration is related to a high number of regulatory T cells and promotes a progressive course of HPV‐induced vulvar neoplasia , 2015, International journal of cancer.

[10]  G. Matarese,et al.  Enrichment of CD56dimKIR+CD57+ highly cytotoxic NK cells in tumor infiltrated lymph nodes of melanoma patients , 2014, Nature Communications.

[11]  R. Emerson,et al.  PD-1 blockade induces responses by inhibiting adaptive immune resistance , 2014, Nature.

[12]  M. Donia,et al.  Simplified protocol for clinical-grade tumor-infiltrating lymphocyte manufacturing with use of the Wave bioreactor. , 2014, Cytotherapy.

[13]  P. Nederlof,et al.  Immune-Escape Markers in Relation to Clinical Outcome of Advanced Melanoma Patients Following Immunotherapy , 2014, Cancer Immunology Research.

[14]  S. H. van der Burg,et al.  Tumor‐infiltrating CD14‐positive myeloid cells and CD8‐positive T‐cells prolong survival in patients with cervical carcinoma , 2013, International journal of cancer.

[15]  S. Zanata,et al.  De novo galectin-3 expression influences the response of melanoma cells to isatin-Schiff base copper (II) complex-induced oxidative stimulus. , 2013, Chemico-biological interactions.

[16]  M. Dominici,et al.  Proinflammatory stimuli induce galectin‐9 in human mesenchymal stromal cells to suppress T‐cell proliferation , 2013, European journal of immunology.

[17]  P. van Endert,et al.  Anticancer chemotherapy-induced intratumoral recruitment and differentiation of antigen-presenting cells. , 2013, Immunity.

[18]  K. Egervari,et al.  Correlation among metallothionein expression, intratumoural macrophage infiltration and the risk of metastasis in human cutaneous malignant melanoma , 2013, Journal of the European Academy of Dermatology and Venereology : JEADV.

[19]  M. Bar‐eli,et al.  The sweet and bitter sides of galectins in melanoma progression , 2012, Pigment cell & melanoma research.

[20]  C. Sautès-Fridman,et al.  The immune contexture in human tumours: impact on clinical outcome , 2012, Nature Reviews Cancer.

[21]  J. Bartlett,et al.  Association of galectin-3 expression with melanoma progression and prognosis. , 2012, European journal of cancer.

[22]  Alison P. Klein,et al.  Colocalization of Inflammatory Response with B7-H1 Expression in Human Melanocytic Lesions Supports an Adaptive Resistance Mechanism of Immune Escape , 2012, Science Translational Medicine.

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

[24]  Rui-Ru Ji,et al.  An immune-active tumor microenvironment favors clinical response to ipilimumab , 2012, Cancer Immunology, Immunotherapy.

[25]  S. H. van der Burg,et al.  Successful treatment of metastatic melanoma by adoptive transfer of blood-derived polyclonal tumor-specific CD4+ and CD8+ T cells in combination with low-dose interferon-alpha , 2011, Cancer Immunology, Immunotherapy.

[26]  P. Courtoy,et al.  A galectin-3 ligand corrects the impaired function of human CD4 and CD8 tumor-infiltrating lymphocytes and favors tumor rejection in mice. , 2010, Cancer research.

[27]  Jeffrey E Gershenwald,et al.  Final version of 2009 AJCC melanoma staging and classification. , 2009, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[28]  K. Drzewiecki,et al.  Spontaneous regression of metastases from melanoma: review of the literature , 2009, Melanoma research.

[29]  Michael Loran Dustin,et al.  Galectin-3 negatively regulates TCR-mediated CD4+ T-cell activation at the immunological synapse , 2009, Proceedings of the National Academy of Sciences.

[30]  H. Møller,et al.  Macrophage markers in serum and tumor have prognostic impact in American Joint Committee on Cancer stage I/II melanoma. , 2009, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[31]  G. Schuler,et al.  Association of gene expression profile in metastatic melanoma and survival to a dendritic cell-based vaccine. , 2009, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[32]  M. Tretiakova,et al.  Chemokine expression in melanoma metastases associated with CD8+ T-cell recruitment. , 2009, Cancer research.

[33]  T. Niki,et al.  Galectin-9 expands unique macrophages exhibiting plasmacytoid dendritic cell-like phenotypes that activate NK cells in tumor-bearing mice. , 2009, Clinical immunology.

[34]  P. Bradding,et al.  Macrophages within NSCLC tumour islets are predominantly of a cytotoxic M1 phenotype associated with extended survival , 2009, European Respiratory Journal.

[35]  T. Niki,et al.  Galectin-9 Increases Tim-3+ Dendritic Cells and CD8+ T Cells and Enhances Antitumor Immunity via Galectin-9-Tim-3 Interactions1 , 2008, The Journal of Immunology.

[36]  Donna Niedzwiecki,et al.  Meta-analysis of phase II cooperative group trials in metastatic stage IV melanoma to determine progression-free and overall survival benchmarks for future phase II trials. , 2008, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[37]  D. Furman,et al.  Tumorigenesis and Neoplastic Progression Galectin-3 Expression Correlates with Apoptosis of Tumor-Associated Lymphocytes in Human Melanoma Biopsies , 2006 .

[38]  S. Szabo,et al.  Antigen-driven effector CD8 T cell function regulated by T-bet , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[39]  S. Yagihashi,et al.  Interferon‐γ stimulates the expression of galectin‐9 in cultured human endothelial cells , 2002, Journal of Leukocyte Biology.

[40]  S. Yagihashi,et al.  Interferon-gamma stimulates the expression of galectin-9 in cultured human endothelial cells. , 2002, Journal of leukocyte biology.

[41]  S. Rosenberg,et al.  Treatment of patients with metastatic melanoma with autologous tumor-infiltrating lymphocytes and interleukin 2. , 1994, Journal of the National Cancer Institute.