Cancer-Associated Fibroblasts in Conversation with Tumor Cells in Endometrial Cancers: A Partner in Crime

A tumor cell carrying characteristic genomic alteration(s) exists within its host’s microenvironment. The tumor microenvironment (TME) renders holistic support to the tumor via cross-talk between tumor cells and three components of TME, immune components, vascular components, and fibroblast components. The tempero-spatial interaction of tumor cells with its microenvironment is the deterministic factor for tumor growth, progression, resistance to therapy, and its outcome in clinics. TME (1) facilitates proliferation, and the ensuing metastasis-associated phenotypes, (2) perturbs immune surveillance and supports tumor cells in their effort to evade immune recognition, and (3) actively participates in developing drug-induced resistance in cancer cells. Cancer-Associated Fibroblast (CAF) is a unique component of TME. CAF is the host mesenchyme immediately surrounding the tumor cells in solid tumors. It facilitates tumor growth and progression and participates in developing drug resistance in tumor cells by playing a critical role in all the ways mentioned above. The clinical outcome of a disease is thus critically contributed to by the CAF component of TME. Although CAFs have been identified historically, the functional relevance of CAF-tumor cell cross-talk and their influence on angiogenic and immune-components of TME are yet to be characterized in solid tumors, especially in endometrial cancers. Currently, the standard of care for the treatment of endometrial cancers is primarily guided by therapies directed towards the disease’s tumor compartment and immune compartments. Unfortunately, in the current state of therapies, a complete response (CR) to the therapy is still limited despite a more commonly achieved partial response (PR) and stable disease (SD) in patients. Acknowledging the limitations of the current sets of therapies based on only the tumor and immune compartments of the disease, we sought to put forward this review based on the importance of the cross-talk between CAF of the tumor microenvironment and tumor cells. The premise of the review is to recognize the critical role of CAF in disease progression. This manuscript presents a systemic review of the role of CAF in endometrial cancers. We critically interrogated the active involvement of CAF in the tumor compartment of endometrial cancers. Here we present the functional characteristics of CAF in the context of endometrial cancers. We review (1) the characteristics of CAF, (2) their evolution from being anti-tumor to pro-tumor, (3) their involvement in regulating growth and several metastasis-associated phenotypes of tumor cells, (4) their participation in perturbing immune defense and evading immune surveillance, and (5) their role in mediating drug resistance via tumor-CAF cross-talk with particular reference to endometrial cancers. We interrogate the functional characteristics of CAF in the light of its dialogue with tumor cells and other components of TME towards developing a CAF-based strategy for precision therapy to supplement tumor-based therapy. The purpose of the review is to present a new vision and initiate a thought process which recognizes the importance of CAF in a tumor, thereby resulting in a novel approach to the design and management of the disease in endometrial cancers.

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Cancer Cell-Derived Granulocyte-Macrophage Colony-Stimulating Factor Is Dispensable for the Progression of 4T1 Murine Breast Cancer

International Journal of Molecular Sciences ◽

10.3390/ijms20246342 ◽

2019 ◽

Vol 20 (24) ◽

pp. 6342

Author(s):

Teizo Yoshimura ◽

Kaoru Nakamura ◽

Chunning Li ◽

Masayoshi Fujisawa ◽

Tsuyoshi Shiina ◽

...

Keyword(s):

Breast Cancer ◽

Tumor Microenvironment ◽

Tumor Growth ◽

Cancer Cell ◽

Lung Metastasis ◽

Cancer Progression ◽

Critical Role ◽

Gm Csf ◽

4T1 Cells

We previously reported that 4T1 murine breast cancer cells produce GM-CSF that up-regulates macrophage expression of several cancer promoting genes, including Mcp-1/Ccl2, Ccl17 and Rankl, suggesting a critical role of cancer cell-derived GM-CSF in cancer progression. Here, we attempted to define whether 4T1 cell-derived GM-CSF contributes to the expression of these genes by 4T1tumors, and their subsequent progression. Intraperitoneal injection of anti-GM-CSF neutralizing antibody did not decrease the expression of Mcp-1, Ccl17 or Rankl mRNA by 4T1 tumors. To further examine the role of cancer cell-derived GM-CSF, we generated GM-CSF-deficient 4T1 cells by using the Crisper-Cas9 system. As previously demonstrated, 4T1 cells are a mixture of cells and cloning of cells by itself significantly reduced tumor growth and lung metastasis. By contrast, GM-CSF-deficiency did not affect tumor growth, lung metastasis or the expression of these chemokine and cytokine genes in tumor tissues. By in-situ hybridization, the expression of Mcp-1 mRNA was detected in both F4/80-expressing and non-expressing cells in tumors of GM-CSF-deficient cells. These results indicate that cancer cell-derived GM-CSF is dispensable for the tuning of the 4T1 tumor microenvironment and the production of MCP-1, CCL17 or RANKL in the 4T1 tumor microenvironment is likely regulated by redundant mechanisms.

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Protease Activated Receptor-1 (PAR-1) Impedes Tumor Progression

Blood ◽

10.1182/blood.v128.22.2560.2560 ◽

2016 ◽

Vol 128 (22) ◽

pp. 2560-2560

Author(s):

Gregory N. Adams ◽

Haley Weston ◽

Leah Rosenfeldt ◽

Malinda Frederick ◽

Joseph S. Palumbo

Keyword(s):

Cell Proliferation ◽

Tumor Growth ◽

Tumor Cell ◽

Tumor Cells ◽

Prostate Tumor ◽

Protease Activated Receptor 1 ◽

Tumor Types ◽

And Control

Abstract Activation of cell signaling by thrombin through Protease Activated Receptor-1 (PAR-1) represents one important interface between blood coagulation and cell activation in response to injury and inflammation. In the context of cancer, PAR-1 has been suggested to promote tumor growth through mechanisms coupled to tumor cell proliferation, tumor cell migration, and the development of a supportive tumor stroma. Consistent with this view, both tumor cells and stromal cells express high levels of PAR-1, and elevated PAR-1 expression has been correlated with a poor prognosis across several tumor types. In the current studies, we tested the hypothesis that PAR-1 is a critical driver of tumorigenesis and tumor growth using murine models of genetically-induced prostate and intestinal tumor growth. To define the role of PAR-1 in prostate tumor progression, we interbred mice expressing the TRAMP transgene (transgenic adenocarcinoma of the mouse prostate; SV40 Large T antigen under the control of a probasin promoter) to PAR-1-deficient mice (PAR-1-/-) in order to generate male TRAMP mice with and without PAR-1 expression for detailed analyses of prostate tumor growth. Surprisingly, prostate tumors harvested from PAR-1-/- mice were significantly larger than those harvested from PAR-1+/+ mice. In order to begin to address the PAR-1 expressing cellular compartments responsible for prostate tumor inhibition, we subcutaneously inoculated immunocompetent C57Bl/6-derived PAR-1-/- and control mice with tumor cells derived from a C57Bl/6 TRAMP mouse. TRAMP-derived tumors grew indistinguishably in PAR-1-/- and control mice, suggesting that stromal-cell associated PAR-1 is dispensable for prostate tumor growth. We next tested the effect of tumor cell-intrinsic inhibition of PAR-1 in TRAMP tumor cells by viral transduction with a construct containing an shRNA against murine PAR-1 in parallel to a non-specific shRNA construct. Diminishing tumor cell-associated PAR-1 expression resulted in significantly more rapid tumor growth in vivo. In order to better define the role of tumor cell-intrinsic PAR-1 we harvested TRAMP tumor cells from a PAR-1 deficient mouse and grew these cells in vitro. We transduced these PAR-1-deficient prostate tumor cells with viral vectors conferring expression of WT murine PAR-1 (PAR-1+), a PAR-1 mutant lacking the thrombin cleavage (R41A mutant) or empty vector (PAR-1-). PAR-1- cells grew robustly and similarly to the parental cells in vitro with a doubling time of approximately 48 hours. Cells expressing the R41A mutant PAR-1 also grew robustly and similarly to PAR-1 deficient cells. However, PAR-1+ cells failed to show any signs of cell proliferation over the span of a 4 day observation period. Furthermore, PAR-1 expression dramatically altered the ability of TRAMP cells to demonstrate signs of cell spreading as measured by the frequency of pseudopodia per cell. As a means of determining the role of PAR-1 in tumorigenesis and tumor growth in another spontaneously occurring setting, we interbred PAR-1-/- mice with APCMin/+ mice genetically predisposed to intestinal adenoma formation due to loss of heterozygosity of the tumor suppressor adenomatous polyposis coli gene. Blinded quantitative histological analyses of the intestinal tracts of PAR-1-/- and PAR-1+/+ APCMin/+ mice revealed that PAR-1 deficiency resulted in a significant 2-fold increase in the number of adenomas observed. Furthermore, the adenomas observed in PAR-1-/- mice were significantly larger based on morphometric analyses of adenoma surface area in histological sections. In sum, these data demonstrate a surprising and unexpected role for PAR-1 in the inhibition of tumor growth in the context of two distinct tumor types. Disclosures No relevant conflicts of interest to declare.

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Leveling Up the Controversial Role of Neutrophils in Cancer: When the Complexity Becomes Entangled

Cells ◽

10.3390/cells10092486 ◽

2021 ◽

Vol 10 (9) ◽

pp. 2486

Author(s):

Ronit Vogt Sionov

Keyword(s):

Tumor Growth ◽

Tumor Cell ◽

Cancer Cells ◽

Tumor Cells ◽

Immune Cell ◽

Neutrophil Function ◽

The Body ◽

Cathepsin G ◽

Metastatic Sites

Neutrophils are the most abundant immune cell in the circulation of human and act as gatekeepers to discard foreign elements that have entered the body. They are essential in initiating immune responses for eliminating invaders, such as microorganisms and alien particles, as well as to act as immune surveyors of cancer cells, especially during the initial stages of carcinogenesis and for eliminating single metastatic cells in the circulation and in the premetastatic organs. Since neutrophils can secrete a whole range of factors stored in their many granules as well as produce reactive oxygen and nitrogen species upon stimulation, neutrophils may directly or indirectly affect carcinogenesis in both the positive and negative directions. An intricate crosstalk between tumor cells, neutrophils, other immune cells and stromal cells in the microenvironment modulates neutrophil function resulting in both anti- and pro-tumor activities. Both the anti-tumor and pro-tumor activities require chemoattraction towards the tumor cells, neutrophil activation and ROS production. Divergence is seen in other neutrophil properties, including differential secretory repertoire and membrane receptor display. Many of the direct effects of neutrophils on tumor growth and metastases are dependent on tight neutrophil–tumor cell interactions. Among them, the neutrophil Mac-1 interaction with tumor ICAM-1 and the neutrophil L-selectin interaction with tumor-cell sialomucins were found to be involved in the neutrophil-mediated capturing of circulating tumor cells resulting in increased metastatic seeding. On the other hand, the anti-tumor function of neutrophils was found to rely on the interaction between tumor-surface-expressed receptor for advanced glycation end products (RAGE) and Cathepsin G expressed on the neutrophil surface. Intriguingly, these two molecules are also involved in the promotion of tumor growth and metastases. RAGE is upregulated during early inflammation-induced carcinogenesis and was found to be important for sustaining tumor growth and homing at metastatic sites. Cathepsin G was found to be essential for neutrophil-supported lung colonization of cancer cells. These data level up the complexity of the dual role of neutrophils in cancer.

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Cancer: An Oxidative Crosstalk between Solid Tumor Cells and Cancer Associated Fibroblasts

BioMed Research International ◽

10.1155/2016/4502846 ◽

2016 ◽

Vol 2016 ◽

pp. 1-7 ◽

Cited By ~ 38

Author(s):

Alessandro Arcucci ◽

Maria Rosaria Ruocco ◽

Giuseppina Granato ◽

Anna Maria Sacco ◽

Stefania Montagnani

Keyword(s):

Tumor Microenvironment ◽

Tumor Growth ◽

Tumor Progression ◽

Cancer Cells ◽

Tumor Cells ◽

Critical Role ◽

Metabolic Reprogramming ◽

Antioxidant Systems ◽

Activation Process ◽

Cancer Associated Fibroblasts

Redox balance is associated with the regulation of several cell signalling pathways and functions. In fact, under physiological conditions, cells maintain a balance between oxidant and antioxidant systems, and reactive oxygen species (ROS) can act as second messengers to regulate cell proliferation, cell death, and other physiological processes. Cancer tissues usually contain higher levels of ROS than normal tissues, and this ROS overproduction is associated with tumor development. Neoplastic tissues are very heterogeneous systems, composed of tumor cells and microenvironment that has a critical role in tumor progression. Cancer associated fibroblasts (CAFs) represent the main cell type of tumor microenvironment, and they contribute to tumor growth by undergoing an irreversible activation process. It is known that ROS can be transferred from cancer cells to fibroblasts. In particular, ROS affect the behaviour of CAFs by promoting the conversion of fibroblasts to myofibroblasts that support tumor progression and dissemination. Furthermore, the wrecking of redox homeostasis in cancer cells and tumor microenvironment induces a metabolic reprogramming in tumor cells and cancer associated fibroblasts, giving advantage to cancer growth. This review describes the role of ROS in tumor growth, by focusing on CAFs activation and metabolic interactions between cancer cells and stromal fibroblasts.

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Advances in Drug Resistance of Esophageal Cancer: From the Perspective of Tumor Microenvironment

Frontiers in Cell and Developmental Biology ◽

10.3389/fcell.2021.664816 ◽

2021 ◽

Vol 9 ◽

Author(s):

Siyuan Luan ◽

Xiaoxi Zeng ◽

Chao Zhang ◽

Jiajun Qiu ◽

Yushang Yang ◽

...

Keyword(s):

Drug Resistance ◽

Esophageal Cancer ◽

Tumor Microenvironment ◽

Tumor Cells ◽

Molecular Mechanisms ◽

Therapeutic Benefit ◽

Therapeutic Agents ◽

Development Of Resistance ◽

Cellular Components

Drug resistance represents the major obstacle to get the maximum therapeutic benefit for patients with esophageal cancer since numerous patients are inherently or adaptively resistant to therapeutic agents. Notably, increasing evidence has demonstrated that drug resistance is closely related to the crosstalk between tumor cells and the tumor microenvironment (TME). TME is a dynamic and ever-changing complex biological network whose diverse cellular and non-cellular components influence hallmarks and fates of tumor cells from the outside, and this is responsible for the development of resistance to conventional therapeutic agents to some extent. Indeed, the formation of drug resistance in esophageal cancer should be considered as a multifactorial process involving not only cancer cells themselves but cancer stem cells, tumor-associated stromal cells, hypoxia, soluble factors, extracellular vesicles, etc. Accordingly, combination therapy targeting tumor cells and tumor-favorable microenvironment represents a promising strategy to address drug resistance and get better therapeutic responses for patients with esophageal cancer. In this review, we mainly focus our discussion on molecular mechanisms that underlie the role of TME in drug resistance in esophageal cancer. We also discuss the opportunities and challenges for therapeutically targeting tumor-favorable microenvironment, such as membrane proteins, pivotal signaling pathways, and cytokines, to attenuate drug resistance in esophageal cancer.

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Extracellular Vesicles and Cancer Stem Cells in Tumor Progression: New Therapeutic Perspectives

International Journal of Molecular Sciences ◽

10.3390/ijms221910572 ◽

2021 ◽

Vol 22 (19) ◽

pp. 10572

Author(s):

Maria Giovanna Scioli ◽

Sonia Terriaca ◽

Elena Fiorelli ◽

Gabriele Storti ◽

Giulia Fabbri ◽

...

Keyword(s):

Stem Cells ◽

Drug Resistance ◽

Cancer Stem Cells ◽

Tumor Growth ◽

Tumor Progression ◽

Extracellular Vesicles ◽

Cross Talk ◽

Cell Populations ◽

Disease Relapse

Tumor burden is a complex microenvironment where different cell populations coexist and have intense cross-talk. Among them, a heterogeneous population of tumor cells with staminal features are grouped under the definition of cancer stem cells (CSCs). CSCs are also considered responsible for tumor progression, drug resistance, and disease relapse. Furthermore, CSCs secrete a wide variety of extracellular vesicles (EVs) with different cargos, including proteins, lipids, ssDNA, dsDNA, mRNA, siRNA, or miRNA. EVs are internalized by other cells, orienting the microenvironment toward a protumorigenic and prometastatic one. Given their importance in tumor growth and metastasis, EVs could be exploited as a new therapeutic target. The inhibition of biogenesis, release, or uptake of EVs could represent an efficacious strategy to impair the cross-talk between CSCs and other cells present in the tumor microenvironment. Moreover, natural or synthetic EVs could represent suitable carriers for drugs or bioactive molecules to target specific cell populations, including CSCs. This review will discuss the role of CSCs and EVs in tumor growth, progression, and metastasis and how they affect drug resistance and disease relapse. Furthermore, we will analyze the potential role of EVs as a target or vehicle of new therapies.

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The Influence of a Stressful Microenvironment on Tumor Exosomes: A Focus on the DNA Cargo

International Journal of Molecular Sciences ◽

10.3390/ijms21228728 ◽

2020 ◽

Vol 21 (22) ◽

pp. 8728

Author(s):

Rossana Domenis ◽

Adriana Cifù ◽

Francesco Curcio

Keyword(s):

Tumor Microenvironment ◽

Tumor Cell ◽

Tumor Cells ◽

Genomic Dna ◽

Bioactive Molecules ◽

Cell Of Origin ◽

Non Invasive ◽

Tumor Exosomes ◽

Production Pattern

Exosomes secreted by tumor cells, through the transport of bioactive molecules, reprogram the surroundings, building a microenvironment to support the development of the tumor. The discovery that exosomes carry genomic DNA reflecting that of the tumor cell of origin has encouraged studies to use them as non-invasive biomarkers. The exosome-mediated transfer of oncogenes suggested a new mechanism of malignant transformation that could play a role in the formation of metastases. Several studies have examined the role of tumor exosomes on the modulation of the tumor microenvironment, but relatively few have been directed to assess how stressful stimuli can influence their production and cargo. Understanding the changes in exosome loads and the production pattern of the stressed tumor cell may uncover actionable mechanisms responsible for tumor progression.

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Extracellular Vesicles: A New Perspective in Tumor Therapy

BioMed Research International ◽

10.1155/2018/2687954 ◽

2018 ◽

Vol 2018 ◽

pp. 1-7 ◽

Cited By ~ 2

Author(s):

Yan-Zi Sun ◽

Jun-Shan Ruan ◽

Zong-Sheng Jiang ◽

Ling Wang ◽

Shao-Ming Wang

Keyword(s):

Cell Growth ◽

Tumor Microenvironment ◽

Tumor Cell ◽

Extracellular Vesicles ◽

Cancer Progression ◽

Immune Therapy ◽

Tumor Therapy ◽

Critical Role ◽

Mesenchymal Transition

In recent years, the study of extracellular vesicles has been booming across various industries. Extracellular vesicles are considered one of the most important physiological endogenous carriers for the specific delivery of molecular information (nucleonic acid, cytokines, enzymes, etc.) between cells. It has been discovered that they perform a critical role in promoting tumor cell growth, proliferation, tumor cell invasion, and metastatic ability and regulating the tumor microenvironment to promote tumor cell communication and metastasis. In this review, we will discuss (1) the mechanism of extracellular vesicles generation, (2) their role in tumorigenesis and cancer progression (cell growth and proliferation, tumor microenvironment, epithelial-mesenchymal transition (EMT), invasion, and metastasis), (3) the role of extracellular vesicles in immune therapy, (4) extracellular vesicles targeting in tumor therapy, and (5) the role of extracellular vesicles as biomarkers. It is our hope that better knowledge and understanding of the extracellular vesicles will offer a wider range of effective therapeutic targets for experimental tumor research.

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Role of Erythropoietin as an Angiogenic Factor and Target in Cancer.

Blood ◽

10.1182/blood.v108.11.416.416 ◽

2006 ◽

Vol 108 (11) ◽

pp. 416-416

Author(s):

Murat O. Arcasoy ◽

Matthew E. Hardee ◽

Xiaohong Jiang ◽

Mark W. Dewhirst

Keyword(s):

Tumor Growth ◽

Tumor Cell ◽

Tumor Cells ◽

Tumor Angiogenesis ◽

Angiogenic Factor ◽

Fat Pad ◽

Significant Stimulation ◽

Mammary Fat Pad ◽

Angiogenic Effect

Abstract Erythropoietin is a pleiotropic cytokine with diverse non-hematopoietic functions. Epo and its receptor EpoR have been implicated in the physiologic angiogenesis that occurs in the mouse embryo, female genital tract and during wound healing. Epo is involved in the pathologic angiogenesis of diabetic retinopathy but the role of Epo in tumor angiogenesis, a pathologic process that is essential for tumor progression, is not established. We investigated the hypothesis that Epo may play an important role in tumor cell-induced angiogenesis and progression. Fluorescently-labeled rodent mammary carcinoma cells were implanted in dorsal skin-fold window chambers in nu/nu mice, a model that allows direct, non-invasive, serial visualization and real-time assessment of tumor cells and neovascularization simultaneously during the initial stages of tumor formation. Tumor angiogenesis (vascular length density, VLD) and growth (tumor area) were measured serially over 8 days using intravital microscopy and computerized image analysis. Co-injection of Epo with implanted tumor cells significantly increased VLD by 78% compared to vehicle-injected controls (p<0.001 by repeated measures ANOVA and Bonferroni test, n=8 mice/group). This early proangiogenic effect was associated with significant stimulation of tumor growth by 66% (p<0.001). Implantation of R3230-GFP cells engineered to stably express a constitutively active EpoR mutant (R129C) resulted in significant stimulation of neovascularization by 76% (p<0.001, n=7) and increased tumor growth by 79% compared to empty vector-transfected control cells (p<0.001). To target endogenous Epo function in window chambers, recombinant soluble EpoR (sEpoR) or a neutralizing anti-Epo monoclonal antibody (mAb) were co-injected at the time of tumor cell implantation. By day 8, marked inhibition of neovascularization was observed in response to treatment with sEpoR (44% reduction) or mAb (47% reduction) compared to vehicle-injected controls (p<0.001, n=7). This anti-angiogenic effect was associated with significant decrease in tumor size by 37% (sEpoR) and 39% (mAb), respectively (p<0.001). Stable expression of a secreted Epo antagonist (Epo-R103A) protein in tumor cells was associated with a remarkable anti-angiogenic effect with 50% reduction in VLD (p<0.001, n=7) and near complete disappearance of tumor cells by day 8 compared to controls (p<0.001). Analysis of two independent single cell clones of each transfected cell line showed similar results. All transfected cell lines exhibited similar in vitro growth characteristics and cell cycle profile. To further assess in vivo tumor growth, cells were implanted orthotopically in the mammary fat pad of female nu/nu mice (10 animals/group). EpoR-R129C expression was associated with significantly increased tumor volume (531±41 mm3, n=10) compared to vector-transfected cells (232±46 mm3, n=7). EpoR-R129C tumors exhibited significantly increased numbers of positive cells for proliferation marker Ki67 and blood vessel marker CD31 per high power field (p=0.0006 and 0.0008, respectively). Remarkably, tumor growth was completely absent after mammary fat pad implantation of R3230-GFP cells secreting the antagonist R103A-Epo protein (n=10 mice) compared to controls (183±46 mm3, n=8). Taken together, these data indicate that 1)-Epo is an important angiogenic factor that modulates tumor cell-induced angiogenesis and 2)-Suppression of tumor angiogenesis and progression by Epo blockade suggests that Epo may constitute a potential target for the therapeutic modulation of angiogenesis in cancer.

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CD80 Expression on Tumor Cells Alters Tumor Microenvironment and Efficacy of Cancer Immunotherapy by CTLA-4 Blockade

Cancers ◽

10.3390/cancers13081935 ◽

2021 ◽

Vol 13 (8) ◽

pp. 1935

Author(s):

Julie Vackova ◽

Ingrid Polakova ◽

Shweta Dilip Johari ◽

Michal Smahel

Keyword(s):

T Cells ◽

Tumor Microenvironment ◽

Tumor Cell ◽

Tumor Cells ◽

Checkpoint Inhibitors ◽

Cell Subset ◽

Treg Cells ◽

Lymphoid Cells ◽

Induced Tumors

Cluster of differentiation (CD) 80 is mainly expressed in immune cells but can also be found in several types of cancer cells. This molecule may either activate or inhibit immune reactions. Here, we determined the immunosuppressive role of CD80 in the tumor microenvironment by CRISPR/Cas9-mediated deactivation of the corresponding gene in the mouse oncogenic TC-1 cell line. The tumor cells with deactivated CD80 (TC-1/dCD80-1) were more immunogenic than parental cells and induced tumors that gained sensitivity to cytotoxic T-lymphocyte antigen 4 (CTLA-4) blockade, as compared with the TC-1 cells. In vivo depletion experiments showed that the deactivation of CD80 switched the pro-tumorigenic effect of macrophages observed in TC-1-induced tumors into an anti-tumorigenic effect in TC-1/dCD80-1 tumors and induced the pro-tumorigenic activity of CD4+ cells. Moreover, the frequency of lymphoid and myeloid cells and the CTLA-4 expression by T helper (Th)17 cells were increased in TC-1/dCD80-1- compared with that in the TC-1-induced tumors. CTLA-4 blockade downregulated the frequencies of most immune cell types and upregulated the frequency of M2 macrophages in the TC-1 tumors, while it increased the frequency of lymphoid cells in TC-1/dCD80-1-induced tumors. Furthermore, the anti-CTLA-4 therapy enhanced the frequency of CD8+ T cells as well as CD4+ T cells, especially for a Th1 subset. Regulatory T cells (Treg) formed the most abundant CD4+ T cell subset in untreated tumors. The anti-CTLA-4 treatment downregulated the frequency of Treg cells with limited immunosuppressive potential in the TC-1 tumors, whereas it enriched this type of Treg cells and decreased the Treg cells with high immunosuppressive potential in TC-1/dCD80-1-induced tumors. The immunosuppressive role of tumor-cell-expressed CD80 should be considered in research into biomarkers for the prediction of cancer patients’ sensitivity to immune checkpoint inhibitors and for the development of a tumor-cell-specific CD80 blockade.

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