A Unique Cellular and Molecular Microenvironment Is Present in Tertiary Lymphoid Organs of Patients with Spontaneous Prostate Cancer Regression

被引:51
作者
Garcia-Hernandez, Maria de la Luz [1 ]
Uribe-Uribe, Norma Ofelia [2 ]
Espinosa-Gonzalez, Ricardo [2 ]
Kast, W. Martin [3 ,4 ,5 ]
Khader, Shabaana A. [6 ]
Rangel-Moreno, Javier [1 ]
机构
[1] Univ Rochester, Dept Med, Rochester, NY 14611 USA
[2] Inst Nacl Ciencias Med & Nutr Salvador Zubiran, Dept Anat & Anat Pathol, Mexico City, DF, Mexico
[3] Univ Southern Calif, Norris Comprehens Canc Ctr, Dept Mol Microbiol & Immunol, Los Angeles, CA USA
[4] Univ Southern Calif, Norris Comprehens Canc Ctr, Dept Urol, Los Angeles, CA USA
[5] Univ Southern Calif, Dept Obstet & Gynecol, Los Angeles, CA USA
[6] Washington Univ, Dept Mol Microbiol, St Louis, MO 63110 USA
来源
FRONTIERS IN IMMUNOLOGY | 2017年 / 8卷
关键词
tertiary lymphoid organs; high endothelial venules; homeostatic chemokines; evanescent prostate carcinoma; cyclooxygenase; 2; prostatic intraepithelial neoplasia; follicular dendritic cells; peripheral node addressin; REGULATORY T-CELLS; 6-TRANSMEMBRANE EPITHELIAL ANTIGEN; INDUCIBLE BALT FORMATION; PULMONARY EXPRESSION; HOMING CHEMOKINES; PROGNOSTIC VALUE; IMMUNE-RESPONSE; TISSUE IBALT; B-CELLS; INFLAMMATION;
D O I
10.3389/fimmu.2017.00563
中图分类号
R392 [医学免疫学]; Q939.91 [免疫学];
学科分类号
100102 ;
摘要
Objective: Multiple solid cancers contain tertiary lymphoid organs (TLO). However, it is unclear whether they promote tumor rejection, facilitate tumor evasion, or simply whether they are a byproduct of chronic inflammation. We hypothesize that although chronic inflammation induces TLO formation, the tumor milieu can modulate TLO organization and functions in prostate cancer. Therefore, our study seeks to elucidate the cellular and molecular signatures in unique prostatectomy specimens from evanescent carcinoma patients to identify markers of cancer regression, which could be harnessed to modulate local immunosuppression or potentially enhance TLO function. Methods: We used multicolor immunofluorescence to stain prostate tissues, collected at different stages of cancer progression (prostatic intraepithelial neoplasia, intermediate and advanced cancer) or from patients with evanescent prostate carcinoma. Tissues were stained with antibodies specific for pro-inflammatory molecules (cyclooxygenase 2, CXCL10, IL17), tumor-infiltrating immune cells (mature DC-LAMP(+) dendritic cells, CD3(+) T cells, CD3(+) Foxp3(+) regulatory T cells (Treg), T bet(+) Th1 cells, granzyme B+ cytotoxic cells), and stromal cell populations (lymphatic vessels, tumor neovessels, high endothelial venules (HEV), stromal cells), which promote prostate tumor growth or are critical components of tumor-associated TLO. Results: Generally, inflammatory cells are located at the margins of tumors. Unexpectedly, we found TLO within prostate tumors from patients at different stages of cancer and in unique samples from patients with spontaneous cancer remission. In evanescent prostate carcinomas, accumulation of Treg was compromised, while Tbet(+) T cells and CD8 T cells were abundant in tumor-associated TLO. In addition, we found a global decrease in tumor neovascularization and the coverage by cells positive for cyclooxygenase 2 (COX2). Finally, consistent with tumor regression, prostate stem cell antigen was considerably reduced in TLO and tumor areas from evanescent carcinoma patients. Conclusion: Collectively, our results suggest that COX2 and Treg are attractive therapeutic targets that can be harnessed to enhance TLO-driven tumor immunity against prostate cancer. Specially, the presence of HEV and lymphatics indicate that TLO can be used as a platform for delivery of cell-based and/or COX2 blocking therapies to improve control of tumor growth in prostate cancer.
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页数:21
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