Cells In Cancer Microenvironment Research Articles

B cell-rich niches support stem-like CD8+ Tcells in cancer microenvironment.

Cytotoxic Tcells are indispensable for the body's fight against most cancers. In the current issue of Cancer Cell, Gaglia etal. reveal how changes in the tumor tissue architecture creating niches of Tcell-B cell interactions may support anti-tumor Tcell responses.

Abstract 3877: A unique layered 3D stromal tissue model for in vitro evaluation of immunologic agents and immune cell infiltration into microenviroment

Abstract Background The modulation of the immune system is a proven key target for cancer therapy, however, the complex interplay between immune cells and cancer cells in cancer microenvironment remains only partially understood. In addition, the currently available in vitro cancer microenvironment models are not designed to study the immunologic agents and a role of immune cells. Here, we developed a unique layered 3D stromal tissue model comprising immune, stromal and cancer cells. Method Layered 3D stromal tissue model was constructed by culturing fibroblasts and endothelial cells coated with extracellular matrix (ECM) and natural polysaccharide. Morphological analysis of the layered 3D stromal tissues and co-cultured tumor were evaluated by HE stain, immunohistochemistry and immunofluorescence (IF). For cytotoxicity assay, cancer cell lines were seeded on or in the 3D stromal tissue and incubated with peripheral blood mononuclear cell (PBMC) and Programmed cell death 1 (PD-1) blockade with Nivolumab. Remaining cancer cells post drug treatment were quantified by IF and imaging analysis. Result The co-cultured stromal tissues were multi-layered (approximately 20 layers), had microvascular formation. Hepatocyte growth factor (HGF) and vascular endothelial growth factor (VEGF) derived from fibroblast cells played important roles in tube formation. Moreover, the position of cancer cells in 3D stromal tissue was manipulated easily. PBMC infiltration into 3D stromal tissue and the interaction between PBMC and cancer cells were visualized. High level of programmed cell death ligand 1 (PD-L1) expression on cancer cells correlated with a higher response to PD-1 blockade in vitro as well as clinical trials. Conclusion We present a unique layered 3D cell culture system based on stromal/cancer/immune cells to study immunologic agents and immune cell infiltration in cancer microenvironment. Our 3D model has the ability to reflect in vivo conditions closer than 2D model and provide a tool for in vitro tumor infiltrating lymphocyte (TIL) or immunologic agent testing. Citation Format: Rii Morimura, Isana Nada, Kei Tsukamoto, Eiji Shinozaki, shiro kitano. A unique layered 3D stromal tissue model for in vitro evaluation of immunologic agents and immune cell infiltration into microenviroment [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3877.

Abstract 1151: A unique layered 3D stromal tissue model for in vitro evaluation of immunologic agents and immune cell infiltration into cancer microenvironment

Abstract Background; The modulation of the immune system is a proven key target for cancer therapy, however, the complex interplay between immune cells and cancer cells in cancer microenvironment remains only partially understood. In addition, the currently available in vitro cancer microenvironment models are not designed to study the immunologic agents and a role of immune cells. Here, we developed a unique layered 3D stromal tissue model comprising an allogeneic immune, stromal and cancer cells. Method; Human umbilical vein endothelial cells (HUVEC) and normal human dermal fibroblasts (NHDF) were coated with collagen and heparin to construct Extracellular matrix (ECM) nanofilm and cultured to form multi-layers. Lung cancer cells were placed between stromal cells. Furthermore, we added Peripheral Blood Mononuclear Cell (PBMC) and Programmed cell death 1 (PD-1) blockade with Nivolumab and evaluated cytotoxic effects of immune cells on cancer cells and immune cell infiltration by immunohistochemistry. Result; The co-cultured stromal tissues were multi-layered (approximately 20 layers), and the presence of lung cancer cells between stromal cells was observed. Immunohistochemistry revealed CD8 positive immune cell infiltration into the fibroblast layers. PBMC with Nivolumab treatment significantly decreased the viability of lung cancer cells in this 3D co-culture compared with the results in 2D mono-culture. High level of programmed cell death ligand 1 (PD-L1) expression on lung cancer cell lines correlated with a higher response to PD-1 blockade in vitro as well as clinical trials. Conclusion; In summary, we present a unique 3D cell culture system based on an allogeneic stromal/cancer/immune cell setting to study immunologic agents and immune cell infiltration in cancer microenvironment. This 3D model has the ability to reflect in vivo conditions closer than 2D model and provide a tool for in vitro immunologic agent testing. Citation Format: Rii Morimura, Kei Tsukamoto, Shiro Kitano, Eiji Shinozaki. A unique layered 3D stromal tissue model for in vitro evaluation of immunologic agents and immune cell infiltration into cancer microenvironment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1151.

Cancer-immune therapy: restoration of immune response in cancer by immune cell modulation

Immune systems play a pivotal role in recognizing cancer and induce effective immune responses for their clearance. Avoidance of immune system is one of the major hallmarks in cancer progression that successively transforms immune surveillance (tumor eradication) to immune tolerance (tumor progression). Modulation of immune cells to harness the power of effective immune responses has been long-term goals for promising strategies of cancer immune therapy. Monoclonal antibodies, immune modulators, vaccines, immune checkpoint blockers are now widely used in cancer immunotherapy. Immunotherapy also provides supportive care against high-dose cancer chemotherapy regimens. Recently immunotherapy was adopted as one of the major approaches during bone marrow transplant of hematologic malignancy. Immune-based therapeutic strategies efficiently restrict tumor evasion and have also shown efficacy against multi-drug resistant cells, one of the most crucial complications in cancer treatment. Advances in immunology and understanding the roles of immune cells in cancer microenvironment have led to numerous specific strategies to boost immune components that successively dampen cancer progression. In this review, we have described several effective immune therapy strategies that target tolerogenic immune cells to become immunogenic and restore immune surveillance in cancer. Manipulation of immune cells by novel therapeutic strategies strive to induce antitumor immune responses by expanding effective anti-tumor T cell immune responses, evoking immune activation signaling and restraining regulatory pathway that established immune-tolerance. The future of cancer immunotherapy relies on a combination of these effective strategies to harness the immune power to restrict cancer advancement.

TGF-β regulates isoform switching of FGF receptors and epithelial-mesenchymal transition

The epithelial-mesenchymal transition (EMT) is a crucial event in wound healing, tissue repair, and cancer progression in adult tissues. Here, we demonstrate that transforming growth factor (TGF)-β induced EMT and that long-term exposure to TGF-β elicited the epithelial-myofibroblastic transition (EMyoT) by inactivating the MEK-Erk pathway. During the EMT process, TGF-β induced isoform switching of fibroblast growth factor (FGF) receptors, causing the cells to become sensitive to FGF-2. Addition of FGF-2 to TGF-β-treated cells perturbed EMyoT by reactivating the MEK-Erk pathway and subsequently enhanced EMT through the formation of MEK-Erk-dependent complexes of the transcription factor δEF1/ZEB1 with the transcriptional corepressor CtBP1. Consequently, normal epithelial cells that have undergone EMT as a result of combined TGF-β and FGF-2 stimulation promoted the invasion of cancer cells. Thus, TGF-β and FGF-2 may cooperate with each other and may regulate EMT of various kinds of cells in cancer microenvironment during cancer progression.