CD8+tumor‐infiltrating lymphocytes at primary sites as a possible prognostic factor of cutaneous angiosarcoma

Tumor‐infiltrating lymphocytes (TILs) have been reported as a prognostic factor in various cancers and are a promising target for immunotherapy. To investigate whether TILs have any impact on the prognosis of angiosarcoma patients, 55 non‐treated patients (40 patients at stage 1 with cutaneous localized tumors, 4 patients at stage 2 with lymph node metastases and 11 patients at stage 3 with distant metastases) with angiosarcoma were evaluated retrospectively by immunohistochemistry stained CD4, CD8, FOXP3 and Ki67. The Kaplan–Meier method was used to estimate overall survival with patients at stage 1. Survival differences were analyzed by the log‐rank test. Patients with higher numbers of CD8+ TILs in their primary tumors survived significantly longer compared with patients with lower values. Moreover, the number of CD8 in TILs was positively correlated with a distant metastasis‐free period. The total number of primary TILs (CD4 plus CD8) and CD8+ primary TILs of stage 3 patients with distant metastases was positively correlated with their overall survival. To evaluate whether CD8+ effector T cells are activated or differentiated, flow cytometric analysis of peripheral blood mononuclear cells (PBMC) was performed. The percentages of CD8+ T cells producing IFN‐γ in PBMC were significantly higher in patients with angiosarcoma (n = 10) compared not only with that of healthy controls (n = 20) but also patients with advanced melanoma (n = 11). These results suggest that anti‐tumor immunity is clinically relevant in angiosarcoma.

[1]  R. Dummer,et al.  Cutaneous angiosarcoma: own experience over 13 years. Clinical features, disease course and immunohistochemical profile , 2010, Journal of the European Academy of Dermatology and Venereology : JEADV.

[2]  S. Rosenberg,et al.  Adoptive cell therapy for the treatment of patients with metastatic melanoma. , 2009, Current opinion in immunology.

[3]  M. Furue,et al.  Usefulness ofintrapleural administration oftumor-infiltrating lymphocytes against massive pleural effusion caused by metastatic angiosarcoma , 1994 .

[4]  George Coukos,et al.  Intratumoral T cells, recurrence, and survival in epithelial ovarian cancer. , 2003, The New England journal of medicine.

[5]  T. Nomura,et al.  Functional delineation and differentiation dynamics of human CD4+ T cells expressing the FoxP3 transcription factor. , 2009, Immunity.

[6]  W. Zou.  Regulatory T cells, tumour immunity and immunotherapy , 2006, Nature Reviews Immunology.

[7]  W. Weninger.  Visualizing intratumoral immune responses , 2007 .

[8]  yang-xin fu,et al.  Tumor-infiltrating T lymphocytes: friends or foes? , 2006, Laboratory Investigation.

[9]  H. Evans,et al.  Angiosarcoma of skin and soft tissue: A study of forty‐four cases , 1981, Cancer.

[10]  Guobin Wang,et al.  Prognostic significance of regulatory T cells in tumor , 2010, International journal of cancer.

[11]  R. Schreiber,et al.  The three Es of cancer immunoediting. , 2004, Annual review of immunology.

[12]  L. Coussens,et al.  Polarized immune responses differentially regulate cancer development , 2008, Immunological reviews.

[13]  F. Marincola,et al.  Cancer classification using the Immunoscore: a worldwide task force , 2012, Journal of Translational Medicine.

[14]  N. Hiraoka.  Tumor-infiltrating lymphocytes and hepatocellular carcinoma: molecular biology , 2010, International Journal of Clinical Oncology.

[15]  M. Masuzawa.  Angiosarcoma of the scalp : Strategy and evaluation at the Kitasato University Hospital , 2009 .

[16]  U. Löhrs,et al.  Inverse relation of Fas-ligand and tumor-infiltrating lymphocytes in angiosarcoma: indications of apoptotic tumor counterattack. , 2001, The American journal of pathology.

[17]  H Nagura,et al.  Proliferative activity of intratumoral CD8(+) T-lymphocytes as a prognostic factor in human renal cell carcinoma: clinicopathologic demonstration of antitumor immunity. , 2001, Cancer research.

[18]  M. Kojiro,et al.  Clinicopathological study on hepatocellular carcinoma with lymphocytic infiltration , 1998, Hepatology.

[19]  H. Yaegashi,et al.  Application of tyramide signal amplification system to immunohistochemistry: A potent method to localize antigens that are not detectable by ordinary method , 1999, Pathology international.

[20]  Andrei Constantinescu,et al.  CD8+ T cell concentration determines their efficiency in killing cognate antigen–expressing syngeneic mammalian cells in vitro and in mouse tissues , 2010, The Journal of experimental medicine.

[21]  C. Charnsangavej,et al.  Successful surgical excision of primary right atrial angiosarcoma , 2011, Journal of cardiothoracic surgery.

[22]  O. Yamasaki,et al.  Treatment of angiosarcoma in Okayama University Hospital : analysis of 18 patients experienced in the past 15 years , 2009 .

[23]  H. Ohtani.  Focus on TILs: Prognostic significance of tumor infiltrating lymphocytes in human bladder cancer. , 2007 .

[24]  G. Willimsky,et al.  Interleukin-7/b7.1-encoding Adenoviruses Induce Rejection of Updated Version Cited Articles Citing Articles E-mail Alerts Interleukin-7/b7.1-encoding Adenoviruses Induce Rejection of Transplanted but Not Nontransplanted Tumors , 2022 .

[25]  H. Ohtani,et al.  Focus on TILs: prognostic significance of tumor infiltrating lymphocytes in human colorectal cancer. , 2007, Cancer immunity.

[26]  P. Sharma,et al.  Focus on TILs: Prognostic significance of tumor infiltrating lymphocytes in human bladder cancer. , 2007, Cancer immunity.

[27]  P. Coulie,et al.  Tumor antigens recognized by T cells. , 1997, Immunology today.

[28]  P. Schlag,et al.  Prognostic significance of activated CD8(+) T cell infiltrations within esophageal carcinomas. , 2001, Cancer research.

[29]  R. Gress,et al.  T cell immune reconstitution following lymphodepletion. , 2007, Seminars in immunology.

[30]  M. Mihm,et al.  Focus on TILs: prognostic significance of tumor infiltrating lymphocytes in human melanoma. , 2009, Cancer immunity.

[31]  G. Dunn,et al.  Focus on TILs: prognostic significance of tumor infiltrating lymphocytes in head and neck cancers. , 2008, Cancer immunity.

[32]  M. Furue,et al.  Immunotherapy for Stewart-Treves syndrome. Usefulness of intrapleural administration of tumor-infiltrating lymphocytes against massive pleural effusion caused by metastatic angiosarcoma. , 1994, Journal of the American Academy of Dermatology.

[33]  Gerd Ritter,et al.  Intraepithelial CD8+ tumor-infiltrating lymphocytes and a high CD8+/regulatory T cell ratio are associated with favorable prognosis in ovarian cancer. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[34]  M. Lotze,et al.  Th1/Th2 balance in cancer, transplantation and pregnancy , 2004, Springer Seminars in Immunopathology.

[35]  S. Rosenberg,et al.  Adoptive immunotherapy for cancer: building on success , 2006, Nature Reviews Immunology.

[36]  G. Plautz,et al.  Infiltration of tumors by systemically transferred tumor-reactive T lymphocytes is required for antitumor efficacy. , 1999, Cancer research.

[37]  S. Rosenberg,et al.  Identification of specific cytolytic immune responses against autologous tumor in humans bearing malignant melanoma. , 1987, Journal of immunology.

[38]  G. Hartmann,et al.  Dendritic cell vaccination in human melanoma: relationships between clinical effects and vaccine parameters , 2010, Pigment cell & melanoma research.

[39]  M. Mansukhani,et al.  The frequent expression of cancer/testis antigens provides opportunities for immunotherapeutic targeting of sarcoma. , 2004, Cancer immunity.

[40]  W. Curry,et al.  Focus on TILs: Prognostic significance of tumor infiltrating lymphocytes in human glioma. , 2007, Cancer immunity.