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

Abstract

ObjectiveMultiple 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.MethodsWe 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.ResultsGenerally, 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.ConclusionCollectively, 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.

BRF1 accelerates prostate tumourigenesis and perturbs immune infiltration

“…3e, f and S5c). Consistent with our previous report [21] and clinical PCa [22], stromal tertiary lymphoid aggregates were present in murine tumours (Fig. S5b), neither the total area of these structures nor markers of Bcell response were unaltered (Figs.…”

“…It is recognised that immune infiltration can have a significant influence upon clinical outcome in cancer patients [22]. Our previous study found that improved survival upon genetic loss of Erk5 in Pten Δ/Δ PCa model was related to increased levels of the T cell recruiting cytokines Ccl5 and Cxcl10 and enhanced T cell infiltration (predominantly CD4 + ) within the tumours [21].…”

Fully Human Antibodies for Malignant Pleural Mesothelioma Targeting

“…In MPM, lymphoid aggregates are present in about 70% of tumors, and GCs within these aggregates can be spotted in about 30% of cases [23]. These aggregates show functional similarity to TLSs, in which T-and B-lymphocytes are apart in two adjacent regions surrounded by HEV, as already shown in ovarian and prostate cancer [93,94]. Despite that, clear evidence of HEV's presence in MPM is still lacking.…”

Deconstructing Immune Microenvironments of Lymphoid Tissues for Reverse Engineering

“…Within most SLOs and TLOs the basic stromal building blocks are fairly consistent, having T‐cell zones with adjacent B‐cell follicles marked within a supporting reticulum, infiltrating vascular ECs and/or LECs in the form of well‐defined vessels. Less well‐formed TLOs have lesser anatomical organization, albeit with similar building blocks, such as those found conjointly with tumors, forming a unique tumor immune microenvironment. The ultimate goal of recreating immune microenvironments, in parts or whole, is to increase knowledge in immunology or immune response by providing test platforms for mechanistic investigations.…”