Cells

Research

18 pages, 3756 KiB

Open AccessArticle

KLK6/PAR1 Axis Promotes Tumor Growth and Metastasis by Regulating Cross-Talk between Tumor Cells and Macrophages

by Yo Sep Hwang, Hee Jun Cho, Eun Sun Park, Jeewon Lim, Hyang Ran Yoon, Jong-Tae Kim, Suk Ran Yoon, Haiyoung Jung, Yong-Kyung Choe, Yong-Hoon Kim, Chul-Ho Lee, Yong Tae Kwon, Bo Yeon Kim and Hee Gu Lee

Cells 2022, 11(24), 4101; https://doi.org/10.3390/cells11244101 - 16 Dec 2022

Cited by 5 | Viewed by 2208

Abstract

Kallikrein-related peptidase (KLK)6 is associated with inflammatory diseases and neoplastic progression. KLK6 is aberrantly expressed in several solid tumors and regulates cancer development, metastatic progression, and drug resistance. However, the function of KLK6 in the tumor microenvironment remains unclear. This study aimed to [...] Read more.

Kallikrein-related peptidase (KLK)6 is associated with inflammatory diseases and neoplastic progression. KLK6 is aberrantly expressed in several solid tumors and regulates cancer development, metastatic progression, and drug resistance. However, the function of KLK6 in the tumor microenvironment remains unclear. This study aimed to determine the role of KLK6 in the tumor microenvironment. Here, we uncovered the mechanism underlying KLK6-mediated cross-talk between cancer cells and macrophages. Compared with wild-type mice, KLK6−/− mice showed less tumor growth and metastasis in the B16F10 melanoma and Lewis lung carcinoma (LLC) xenograft model. Mechanistically, KLK6 promoted the secretion of tumor necrosis factor-alpha (TNF-α) from macrophages via the activation of protease-activated receptor-1 (PAR1) in an autocrine manner. TNF-α secreted from macrophages induced the release of the C-X-C motif chemokine ligand 1 (CXCL1) from melanoma and lung carcinoma cells in a paracrine manner. The introduction of recombinant KLK6 protein in KLK6−/− mice rescued the production of TNF-α and CXCL1, tumor growth, and metastasis. Inhibition of PAR1 activity suppressed these malignant phenotypes rescued by rKLK6 in vitro and in vivo. Our findings suggest that KLK6 functions as an important molecular link between macrophages and cancer cells during malignant progression, thereby providing opportunities for therapeutic intervention. Full article

(This article belongs to the Special Issue Tumor Immune Microenvironment for Effective Therapy)

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14 pages, 2003 KiB

Open AccessArticle

Tumor-Induced T Cell Polarization by Schwann Cells

by Galina V. Shurin, Kavita Vats, Oleg Kruglov, Yuri L. Bunimovich and Michael R. Shurin

Cells 2022, 11(22), 3541; https://doi.org/10.3390/cells11223541 - 9 Nov 2022

Cited by 6 | Viewed by 2244

Abstract

Nerve-cancer crosstalk resulting in either tumor neurogenesis or intratumoral neurodegeneration is critically controlled by Schwann cells, the principal glial cells of the peripheral nervous system. Though the direct stimulating effect of Schwann cells on malignant cell proliferation, motility, epithelial–mesenchymal transition, and the formation [...] Read more.

Nerve-cancer crosstalk resulting in either tumor neurogenesis or intratumoral neurodegeneration is critically controlled by Schwann cells, the principal glial cells of the peripheral nervous system. Though the direct stimulating effect of Schwann cells on malignant cell proliferation, motility, epithelial–mesenchymal transition, and the formation of metastases have been intensively investigated, the ability of Schwann cells to affect the effector and regulatory immune cells in the tumor environment is significantly less studied. Here, we demonstrated that tumor cells could stimulate Schwann cells to produce high levels of prostaglandin E, which could be blocked by COX-2 inhibitors. This effect was mediated by tumor-derived TGF-β as neutralization of this cytokine in the tumor-conditioned medium completely blocked the inducible prostaglandin E production by Schwann cells. Similar protective effects were also induced by the Schwann cell pretreatment with TGF-βR1/ALK4/5/7 and MAPK/ERK kinase inhibitors of the canonical and non-canonical TGF-β signaling pathways, respectively. Furthermore, prostaglandin E derived from tumor-activated Schwann cells blocked the proliferation of CD3/CD28-activated T cells and upregulated the expression of CD73 and PD-1 on both CD4+ and CD8+ T cells, suggesting T cell polarization to the exhausted phenotype. This new pathway of tumor-induced T cell inhibition via the activation of neuroglial cells represents new evidence of the importance of nerve–cancer crosstalk in controlling tumor development and progression. A better understanding of the tumor-neuro-immune axis supports the development of efficient targets for harnessing this axis and improving the efficacy of cancer therapy. Full article

(This article belongs to the Special Issue Tumor Immune Microenvironment for Effective Therapy)

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13 pages, 1838 KiB

Open AccessArticle

CCL22-Polarized TAMs to M2a Macrophages in Cervical Cancer In Vitro Model

by Qun Wang, Kritika Sudan, Elisa Schmoeckel, Bernd Peter Kost, Christina Kuhn, Aurelia Vattai, Theresa Vilsmaier, Sven Mahner, Udo Jeschke and Helene Hildegard Heidegger

Cells 2022, 11(13), 2027; https://doi.org/10.3390/cells11132027 - 25 Jun 2022

Cited by 10 | Viewed by 3166

Abstract

Macrophages are dynamic cells susceptible to the local microenvironment which includes tumor-associated macrophages (TAMs) in cancers. TAMs are a collection of heterogeneous macrophages, including M1 and M2 subtypes, shaped by various activation modes and labeled with various markers in different tumors. CCL22+-infiltrating cells [...] Read more.

Macrophages are dynamic cells susceptible to the local microenvironment which includes tumor-associated macrophages (TAMs) in cancers. TAMs are a collection of heterogeneous macrophages, including M1 and M2 subtypes, shaped by various activation modes and labeled with various markers in different tumors. CCL22+-infiltrating cells are thought to be significantly associated with the prognosis of cervical cancer patients. Moreover, CCL22 is an established marker of M2a macrophages. Although the phenotypic identification of M1 and M2 macrophages is well established in mice and human macrophages cultured in a medium with fetal calf serum (FCS), fewer studies have focused on M2 subtypes. In addition, the question of whether CCL22 affects polarization of M2a macrophages remains unanswered. This study constructed a co-culture system to shape TAMs in vitro. We found that CCL22 was mainly secreted by TAMs but not cervical cancer cell lines. Human peripheral blood monocytes were differentiated into uncommitted macrophages (M0) and then polarized to M1, M2a, M2b, and M2c macrophages using LPS plus IFNr, IL-4, LPS plus IL1β, and IL-10, respectively. Using flowcytometry, we found CD80++ was the marker of M1 and M2b, CD206++ was the marker of M2a, and CD163++ was the marker of M2c, compared with M0 macrophages. By regulating CCL22, we found that the mean fluorescence intensity (MFI) of CD206 in TAMs was significantly affected compared to the control group. Therefore, CCL22 could polarize TAMs of cervical cancer toward M2a macrophages. In conclusion, our study revealed that CCL22 could be a therapeutic target for cervical cancer, which might be because of its role in regulating macrophage polarization. Full article

(This article belongs to the Special Issue Tumor Immune Microenvironment for Effective Therapy)

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20 pages, 6419 KiB

Open AccessArticle

Immune Microenvironment of Muscular-Invasive Urothelial Carcinoma: The Link to Tumor Immune Cycle and Prognosis

by Oleksandr Stakhovskyi, Nazarii Kobyliak, Oleg Voylenko, Eduard Stakhovskyi, Roman Ponomarchuk and Oksana Sulaieva

Cells 2022, 11(11), 1802; https://doi.org/10.3390/cells11111802 - 31 May 2022

Cited by 1 | Viewed by 2240

Abstract

In this study, we investigated the relationship between the tumor immune microenvironment (TIME), histological differentiation and hypoxia in patients with muscular-invasive urothelial carcinomas (MIUC) after radical cystectomy. Forty-two cases of pT2-3N0M0 MIUCs underwent clinical, histological and immunohistochemical evaluation by counting CD8+, FOXP3+, CD68+, [...] Read more.

In this study, we investigated the relationship between the tumor immune microenvironment (TIME), histological differentiation and hypoxia in patients with muscular-invasive urothelial carcinomas (MIUC) after radical cystectomy. Forty-two cases of pT2-3N0M0 MIUCs underwent clinical, histological and immunohistochemical evaluation by counting CD8+, FOXP3+, CD68+, CD163+ cells and polymorphonuclear leukocytes (PMN) in intra-tumoral and peritumoral areas, assessing PD-L1 and GLUT1 expression for defining the impact of tumor immune contexture on patients’ outcomes. Five-year survival rates and overall survival were calculated. Most of the MIUCs demonstrated the immune-desert or immune-excluded TIME, reflecting altered mechanisms of T-cells’ activation or traffic into tumors. Tumor immune contexture was closely related to histological differentiation. CD8+ cells were scant in MIUCs with papillary and squamous differentiation, while basal-like or mesenchymal-like histological differentiation was associated with increased density of CD8+ cells. A high rate of PD-L1 expression (47.6%) was not related to immune cell infiltration. M2-macrophages predominated under CD8+ lymphocytes. The abundance of PMN and CD163+ macrophages in MIUCs was associated with high GLUT1 expression. CD8+, CD68+, FOXP3+ cells and PD-L1 status did not affect patients’ outcomes, while high CD163+ density and PMN infiltration were associated with the unfavorable outcome of patients with MIUC. These data drive the hypothesis that in MIUC, immune escape mechanisms are shifted towards the role of the innate immunity cells rather than CD8+ lymphocytes’ functioning. Full article

(This article belongs to the Special Issue Tumor Immune Microenvironment for Effective Therapy)

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Review

Jump to: Research, Other

29 pages, 2069 KiB

Open AccessFeature PaperReview

Effects of TP53 Mutations and miRs on Immune Responses in the Tumor Microenvironment Important in Pancreatic Cancer Progression

by James A. McCubrey, Li V. Yang, Stephen L. Abrams, Linda S. Steelman, Matilde Y. Follo, Lucio Cocco, Stefano Ratti, Alberto M. Martelli, Giuseppa Augello and Melchiorre Cervello

Cells 2022, 11(14), 2155; https://doi.org/10.3390/cells11142155 - 9 Jul 2022

Cited by 13 | Viewed by 3937

Abstract

Approximately 90% of pancreatic cancers are pancreatic ductal adenocarcinomas (PDAC). PDAC is the fourth leading cause of cancer death world-wide. Therapies for PDAC are largely ineffective due to the dense desmoplastic tumor microenvironment which prevents chemotherapeutic drugs and small molecule inhibitors from exerting [...] Read more.

Approximately 90% of pancreatic cancers are pancreatic ductal adenocarcinomas (PDAC). PDAC is the fourth leading cause of cancer death world-wide. Therapies for PDAC are largely ineffective due to the dense desmoplastic tumor microenvironment which prevents chemotherapeutic drugs and small molecule inhibitors from exerting effective anti-cancer effects. In this review, we will discuss the roles of TP53 and miRs on the PDAC tumor microenvironment and how loss of the normal functions of TP53 promote tumor progression. The TP53 gene is mutated in approximately 50% of pancreatic cancers. Often, these TP53 mutations are point mutations which confer additional functions for the TP53 proteins. These are called gain of function (GOF) mutations (mut). Another class of TP53 mutations are deletions which result in loss of the TP53 protein; these are referred to TP53-null mutations. We have organized this review into various components/properties of the PDAC microenvironment and how they may be altered in the presence of mutant TP53 and loss of certain miR expression. Full article

(This article belongs to the Special Issue Tumor Immune Microenvironment for Effective Therapy)

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13 pages, 554 KiB

Open AccessReview

Complex Role of Microbiome in Pancreatic Tumorigenesis: Potential Therapeutic Implications

by Suneetha Amara, Li V. Yang, Venkataswarup Tiriveedhi and Mahvish Muzaffar

Cells 2022, 11(12), 1900; https://doi.org/10.3390/cells11121900 - 11 Jun 2022

Cited by 3 | Viewed by 2483

Abstract

Pancreatic cancer (PC) is the fourth leading cause of cancer-related mortality with limited diagnostic and therapeutic options. Although immunotherapy has shown promise in the treatment of several cancers, its role in pancreatic cancer is rather limited. Several studies have focused on determining the [...] Read more.

Pancreatic cancer (PC) is the fourth leading cause of cancer-related mortality with limited diagnostic and therapeutic options. Although immunotherapy has shown promise in the treatment of several cancers, its role in pancreatic cancer is rather limited. Several studies have focused on determining the role of the tumor microenvironment with cancer-cell-intrinsic events and tumor-infiltrating immune cellular properties. However, in the past decade, there has been emerging research aimed at delineating the role of the host microbiome, including the metabolites from microbes and host responses, on pancreatic tumorigenesis. Importantly, there is emerging evidence suggesting the beneficial role of a gut microbiome transplant to improve immunotherapeutic outcomes in cancer patients. In this review, we summarize the recent understanding of the role of the microbiome in pancreatic cancer progression, along with its clinical diagnostic and therapeutic implications. Full article

(This article belongs to the Special Issue Tumor Immune Microenvironment for Effective Therapy)

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19 pages, 1664 KiB

Open AccessReview

Immune Cells in Hyperprogressive Disease under Immune Checkpoint-Based Immunotherapy

by Zhanqi Wei and Yuewei Zhang

Cells 2022, 11(11), 1758; https://doi.org/10.3390/cells11111758 - 27 May 2022

Cited by 4 | Viewed by 2341

Abstract

Immunotherapy, an antitumor therapy designed to activate antitumor immune responses to eliminate tumor cells, has been deeply studied and widely applied in recent years. Immune checkpoint inhibitors (ICIs) are capable of preventing the immune responses from being turned off before tumor cells are [...] Read more.

Immunotherapy, an antitumor therapy designed to activate antitumor immune responses to eliminate tumor cells, has been deeply studied and widely applied in recent years. Immune checkpoint inhibitors (ICIs) are capable of preventing the immune responses from being turned off before tumor cells are eliminated. ICIs have been demonstrated to be one of the most effective and promising tumor treatments and significantly improve the survival of patients with multiple tumor types. However, low effective rates and frequent atypical responses observed in clinical practice limit their clinical applications. Hyperprogressive disease (HPD) is an unexpected phenomenon observed in immune checkpoint-based immunotherapy and is a challenge facing clinicians and patients alike. Patients who experience HPD not only cannot benefit from immunotherapy, but also experience rapid tumor progression. However, the mechanisms of HPD remain unclear and controversial. This review summarized current findings from cell experiments, animal studies, retrospective studies, and case reports, focusing on the relationships between various immune cells and HPD and providing important insights for understanding the pathogenesis of HPD. Full article

(This article belongs to the Special Issue Tumor Immune Microenvironment for Effective Therapy)

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Other

Jump to: Research, Review

7 pages, 229 KiB

Open AccessCommentary

Liquid Biopsy and the Translational Bridge from the TIME to the Clinic

by Paul Walker

Cells 2022, 11(19), 3114; https://doi.org/10.3390/cells11193114 - 3 Oct 2022

Viewed by 1156

Abstract

Research and advancing understanding of the tumor immune microenvironment (TIME) is vital to optimize and direct more effective cancer immune therapy. Pre-clinical bench research is vital to better understand the genomic interplay of the TIME and immune therapy responsiveness. However, a vital key [...] Read more.

Research and advancing understanding of the tumor immune microenvironment (TIME) is vital to optimize and direct more effective cancer immune therapy. Pre-clinical bench research is vital to better understand the genomic interplay of the TIME and immune therapy responsiveness. However, a vital key to effective translational cancer research is having a bridge of translation to bring that understanding from the bench to the bedside. Without that bridge, research into the TIME will lack an efficient and effective translation into the clinic and cancer treatment decision making. As a clinical oncologist, the purpose of this commentary is to emphasize the importance of researching and improving clinical utility of the bridge, as well as the TIME research itself. Full article

(This article belongs to the Special Issue Tumor Immune Microenvironment for Effective Therapy)

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