scholarly journals Tumor Cells and Tumor-Associated Macrophages: Secreted Proteins as Potential Targets for Therapy

2011 ◽  
Vol 2011 ◽  
pp. 1-12 ◽  
Author(s):  
Marc Baay ◽  
Anja Brouwer ◽  
Patrick Pauwels ◽  
Marc Peeters ◽  
Filip Lardon
Keyword(s):  
Tumor Growth ◽  
Tumor Cells ◽  
Immune Cells ◽  
Significant Part ◽  
Secreted Proteins ◽  
Tumor Associated Macrophages ◽  
Inflammatory Pathways ◽  
Alternative Phenotype ◽  
Tumor Growth And Metastasis

Inflammatory pathways, meant to defend the organism against infection and injury, as a byproduct, can promote an environment which favors tumor growth and metastasis. Tumor-associated macrophages (TAMs), which constitute a significant part of the tumor-infiltrating immune cells, have been linked to the growth, angiogenesis, and metastasis of a variety of cancers, most likely through polarization of TAMs to the M2 (alternative) phenotype. The interaction between tumor cells and macrophages provides opportunities for therapy. This paper will discuss secreted proteins as targets for intervention.

scholarly journals IL-35 Regulates the Function of Immune Cells in Tumor Microenvironment

2021 ◽  
Vol 12 ◽  
Author(s):  
Kewei Liu ◽  
Ai Huang ◽  
Jun Nie ◽  
Jun Tan ◽  
Shijie Xing ◽  
...  
Keyword(s):  
Tumor Microenvironment ◽  
Tumor Growth ◽  
Immune Cells ◽  
Immune Checkpoint Blockade ◽  
Future Research ◽  
Barr Virus ◽  
Promote Tumor Growth ◽  
Epstein Barr ◽  
Mechanistic Basis ◽  
Tumor Growth And Metastasis

Interleukin-35 (IL-35) is a heterodimeric cytokine composed of Epstein-Barr virus-induced gene 3 (EBI3) and IL-12p35 that has recently been shown to play diverse and important roles in the tumor microenvironment (TME). Owing to its immunosuppressive activity and ability to promote tumor growth and progression, IL-35 is widely recognized as a key mediator of TME status. Immune cells are key mediators of diverse tumor-related phenotypes, and immunosuppressive cytokines such as IL-35 can promote tumor growth and metastasis in TME. These influences should be considered together. Since tumor immunotherapy based on immune checkpoint blockade remains ineffective in many patients due to tumoral resistance, a new target or efficacy enhancing factor is urgently needed. Suppressing IL-35 production and activity has been demonstrated as an effective factor that inhibits tumor cells viability, and further investigation of this cytokine is warranted. However, the mechanistic basis for IL-35-mediated regulation of immune cells in the TME remains to be fully clarified. In the present review, we explore the roles of IL-35 in regulating immune cells within the TME. In addition, we highlight IL-35 as a specific immunological target and discuss its possible relevance in the context of immunotherapy. Lastly, we sought to summarize potential future research directions that may guide the advancement of current understanding regarding the role of this important cytokine as a regulator of oncogenesis.

scholarly journals Strategies to Interfere with Tumor Metabolism through the Interplay of Innate and Adaptive Immunity

Cells ◽  
2019 ◽  
Vol 8 (5) ◽  
pp. 445 ◽  
Author(s):  
Javier Mora ◽  
Christina Mertens ◽  
Julia K. Meier ◽  
Dominik C. Fuhrmann ◽  
Bernhard Brüne ◽  
...  
Keyword(s):  
Tumor Growth ◽  
Tumor Cells ◽  
Immune Cells ◽  
Tumor Development ◽  
Metabolic Activation ◽  
Growth And Survival ◽  
Metabolic Characteristics ◽  
Inflammatory Phenotype ◽  
Tumor Outgrowth

The inflammatory tumor microenvironment is an important regulator of carcinogenesis. Tumor-infiltrating immune cells promote each step of tumor development, exerting crucial functions from initiation, early neovascularization, to metastasis. During tumor outgrowth, tumor-associated immune cells, including myeloid cells and lymphocytes, acquire a tumor-supportive, anti-inflammatory phenotype due to their interaction with tumor cells. Microenvironmental cues such as inflammation and hypoxia are mainly responsible for creating a tumor-supportive niche. Moreover, it is becoming apparent that the availability of iron within the tumor not only affects tumor growth and survival, but also the polarization of infiltrating immune cells. The interaction of tumor cells and infiltrating immune cells is multifaceted and complex, finally leading to different activation phenotypes of infiltrating immune cells regarding their functional heterogeneity and plasticity. In recent years, it was discovered that these phenotypes are mainly implicated in defining tumor outcome. Here, we discuss the role of the metabolic activation of both tumor cells and infiltrating immune cells in order to adapt their metabolism during tumor growth. Additionally, we address the role of iron availability and the hypoxic conditioning of the tumor with regard to tumor growth and we describe the relevance of therapeutic strategies to target such metabolic characteristics.

scholarly journals The Role of Tumor-Associated Macrophages in Leukemia

2019 ◽  
Vol 143 (2) ◽  
pp. 112-117 ◽  
Author(s):  
Yueyang Li ◽  
M. James You ◽  
Yaling Yang ◽  
Dongzhi Hu ◽  
Chen Tian
Keyword(s):  
Stem Cells ◽  
Innate Immunity ◽  
Mesenchymal Stem Cells ◽  
Immune Cells ◽  
Leukemia Cell ◽  
Tumor Associated Macrophages ◽  
Intrinsic Factors ◽  
Different Types ◽  
Tumor Growth And Metastasis

In addition to intrinsic factors, leukemia cell growth is influenced by the surrounding nonhematopoietic cells in the leukemic microenvironment, including fibroblasts, mesenchymal stem cells, vascular cells, and various immune cells. Despite the fact that macrophages are an important component of human innate immunity, tumor-associated macrophages (TAMs) have long been considered as an accomplice promoting tumor growth and metastasis. TAMs are activated by an abnormal malignant microenvironment, polarizing into a specific phenotype and participating in tumor progression. TAMs that exist in the microenvironment of different types of leukemia are called leukemia-associated macrophages (LAMs), which are reported to be associated with the progression of leukemia. This review describes the role of LAMs in different leukemia subtypes.

The spatial localization of CD163+ tumor-associated macrophages predicts prognosis and response to therapy in inflammatory breast cancer.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 3086-3086
Author(s):  
Christophe Van Berckelaer ◽  
Charlotte Rypens ◽  
Steven Van Laere ◽  
Koen Marien ◽  
Pieter-Jan Van Dam ◽  
...  
Keyword(s):  
Breast Cancer ◽  
T Cells ◽  
Deep Learning ◽  
Tumor Cells ◽  
Inflammatory Breast Cancer ◽  
Immune Cells ◽  
Multivariate Model ◽  
Response To Therapy ◽  
Tumor Associated Macrophages ◽  
Cd8 Cells

3086 Background: The mechanisms contributing to the aggressive biology of inflammatory breast cancer (IBC) are under investigation. A specific immune response seems to be an important driver, but the functional role of infiltrating immune cells in IBC remains unclear. Tumor-associated macrophages (TAMs) are associated with worse outcome, while CD8+ cytotoxic T cells demonstrate anti-tumor properties in breast cancer. In this study, we assessed spatial associations between CD163+ TAMs, CD8+ cells and cancer cells in IBC, using deep-learning and ecological statistics. Methods: We collected clinicopathological variables, evaluated PDL1-positivity (SP142, Ventana) and scored TILs according to the TIL working group guidelines on H&E slides for 144 IBC patients. Immunostainings for CD8 and CD163 (Hematoxylin-DAB) were done according to validated protocols. All slides were digitized, underwent virtual multiplexing and were evaluated in Visiopharm to quantify the number of DAB+ immune cells. Each immune cell was located using XY coordinates and spatial interactions were examined using a Morisita Horn Index (MHI). Tumor cell coordinates were collected using a deep-learning algorithm applied to the CD8-stained slide. This algorithm was trained in 18 images with more than 150.000 iterations (Deeplabv3+). Results: Complete pathological response (pCR) after neo-adjuvant chemotherapy was achieved by 30.6% (n= 30/98) of the patients with initially localized disease. Besides PDL1-postivity ( P= .03), infiltration with CD8+ T cells ( P= .02) and TAMs ( P= .01) also predicted pCR. However, a likelihood ratio test showed no difference between a model using CD8+ cells, TAMs or TILs. Interestingly, the colocalization of CD163+ and CD8+ cells (MHI >0.83) was associated with pCR (P= .01) and remained significant in a multivariate model (OR: 3.18; 95% CI: 1.04 – 10.6; P= .05) including TIL score, PDL1-positivity and hormone receptor (HR) status. Furthermore, a shorter disease-free survival (DFS) was associated with HR- status, no pCR and the colocalization of TAMs near tumor cells (HR: 3.3; 95% CI: 1.6 – 7.1; P= .002) in a multivariate model. The density of TAMs was not associated with outcome. Conclusions: The impact of TAMs on clinical outcome appears to depend on the spatial arrangement. The number of TAMs solely was not associated with outcome, but patients with more TAMs in proximity of the tumor cells had a worse DFS. Surprisingly, the clustering of TAMs near CD8+ cells was associated with pCR independent of the number of TAMs or TILs.

scholarly journals Combinations of TLR Ligands: A Promising Approach in Cancer Immunotherapy

2013 ◽  
Vol 2013 ◽  
pp. 1-14 ◽  
Author(s):  
Saskia Stier ◽  
Claudia Maletzki ◽  
Ulrike Klier ◽  
Michael Linnebacher
Keyword(s):  
Tumor Growth ◽  
Tumor Cells ◽  
Cell Lines ◽  
Immune Cells ◽  
Human Lymphocytes ◽  
Growth Control ◽  
Poly I:C ◽  
The Impact

Toll-like receptors (TLRs), a family of pattern recognition receptors recognizing molecules expressed by pathogens, are typically expressed by immune cells. However, several recent studies revealed functional TLR expression also on tumor cells. Their expression is a two-sided coin for tumor cells. Not only tumor-promoting effects of TLR ligands are described but also direct oncopathic and immunostimulatory effects. To clarify TLRs’ role in colorectal cancer (CRC), we tested the impact of the TLR ligands LPS, Poly I:C, R848, and Taxol on primary human CRC cell lines (HROC40, HROC60, and HROC69)in vitroandin vivo(CT26). Taxol, not only a potent tumor-apoptosis-inducing, but also TLR4-activating chemotherapeutic compound, inhibited growth and viability of all cell lines, whereas the remaining TLR ligands had only marginal effects (R848 > LPS > Poly I:C). Combinations of the substances here did not improve the results, whereas antitumoral effects were dramatically boosted when human lymphocytes were added. Here, combining the TLR ligands often diminished antitumoral effects.In vivo, best tumor growth control was achieved by the combination of Taxol and R848. However, when combined with LPS, Taxol accelerated tumor growth. These data generally prove the potential of TLR ligands to control tumor growth and activate immune cells, but they also demonstrate the importance of choosing the right combinations.

SPATIAL AND MECHANOEMISSION CHAOS OF MECHANICALLY DEFORMED TUMOR CELLS

2003 ◽  
Vol 03 (03n04) ◽  
pp. 337-350
Author(s):  
VALERIY E. OREL ◽  
YURI A. GRINEVICH ◽  
NATALIYA N. DZYATKOVSKAYA ◽  
MICHAIL I. DANKO ◽  
ANDRIY V. ROMANOV ◽  
...  
Keyword(s):  
Tumor Growth ◽  
Tumor Cells ◽  
Deterministic Chaos ◽  
Malignant Growth ◽  
Melanoma B16 ◽  
Spatial Chaos ◽  
Non Linear ◽  
Mechanochemical Interaction ◽  
Lewis Carcinoma ◽  
Tumor Growth And Metastasis

The development and spend of the tumor process is accompanied by changes in non-linear (chaotic) dynamics of mechanochemical interaction process in the group of cells. Taking into consideration spatial irregularity and heterogeneity of internal structures of tumor cells, we suggested that treatment by mechanically deformed (MD) syngeneic tumor cells (STC) would be accompanied by changed influence on malignant growth. The objective of this work was to compare spatial, mechanoemission (ME) chaos of MD STC of carcinoma Lewis and melanoma B16 and their malignant growth. MD STC preparation included the aseptic removal of the animal tumor, lyophilization and next mechanical deformation in the microvibratory mill. The suspension of non-deformed or MD STC was injected intraperitoneally. Morphological, morphometric and mechanoemission studies were used for the estimate of spatial chaos and heterogeneity structure in tumor cells and blood. For Lewis carcinoma, the reduction of spatial and ME chaos of cells is accompanied by regression in tumor growth and metastasis. For melanoma B16, the decrease of spatial chaos and the increase of ME chaos in cells are accompanied by the initiation of tumor growth and metastasis. These results illustrated equivalent tendencies in chaos changing in spatial and ME chaos for carcinoma Lewis, while opposite tendencies were observed for melanoma B16. Blood ME of mice with melanoma B16 have greater ME chaos in comparison with animals with Lewis carcinoma. This confirmed that the concept of deterministic chaos is hierarchical for the host during cancer process. Results of comparative analysis between spatial, mechanoemission chaos of MD STC and malignant growth could be useful to gain a better understanding relationship of non-linear biomechanical processes to tumor cells.

scholarly journals IL-4 receptor targeting as an effective immunotherapy against triple-negative breast cancer

2020 ◽  
Author(s):  
Sadiya Parveen ◽  
Sumit Siddharth ◽  
Laurene S Cheung ◽  
Alok Kumar ◽  
John R Murphy ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Tumor Growth ◽  
Triple Negative Breast Cancer ◽  
Immune Cells ◽  
Diphtheria Toxin ◽  
Triple Negative ◽  
Protein Toxin ◽  
Tumor Growth And Metastasis ◽  
Anti Tumor Activity

ABSTRACTIn many solid tumors including triple-negative breast cancer (TNBC), IL-4 receptor (IL-4R) upregulation has been shown to promote cancer cell proliferation, apoptotic resistance, metastatic potential and a Th2 response in the tumor microenvironment (TME). Immunosuppressive cells in the TME including myeloid-derived suppressor cells (MDSCs) and tumor-associated macrophages (TAMs) also express the IL4-R. We hypothesized that selective depletion of IL4-R bearing cells in TNBC may have dual cytotoxic and immunotherapeutic benefit. To selectively target IL-4R+ cells, we genetically constructed, expressed and purified DABIL-4, a fusion protein toxin consisting of the catalytic and translocation domains of diphtheria toxin fused to murine IL-4. We found that DABIL-4 has potent and specific cytotoxic activity against TNBC cells in vitro. In murine TNBC models, DABIL-4 significantly reduced tumor growth, splenomegaly and lung metastases, and this was associated with reductions in MDSC, TAM and regulatory T-cells (Tregs) populations with a concomitant increase in the proportion of IFNγ+ CD8 T-cells. The anti-tumor activity of DABIL-4 was absent in IL-4R KO mice directly implicating IL-4R directed killing as the mechanism of anti-tumor activity. Moreover, NanoString analysis of DABIL-4 treated TNBC tumors revealed marked decline in mRNA transcripts that promote tumorigenesis and metastasis. Our findings demonstrate that DABIL-4 is a potent targeted antitumor agent which depletes both IL-4R bearing tumor cells as well as immunosuppressive cell populations in the TME.STATEMENT OF SIGNIFICANCEIn solid tumors like breast cancer, Interleukin-4 receptor (IL-4R) expression in the tumor microenvironment aids tumor growth and metastasis. IL-4R expression upon host immune cells further dampens antitumor immunity. In this study, we have genetically constructed a fusion protein toxin, DABIL-4, composed of the catalytic and translocation domains of diphtheria toxin and murine IL-4. DABIL-4 showed specific cytotoxicity against triple-negative breast cancer (TNBC) cells in vitro. DABIL-4 also markedly inhibited TNBC tumor growth and metastasis in vivo. The primary activity of DABIL-4 was found to be depletion of IL-4R+ immune cells in combination with direct elimination of tumor cells. In conclusion, DABIL-4 targeting of both tumor and immunosuppressive host cells is a versatile and effective treatment strategy for TNBC.

scholarly journals The Cardioprotective Protein Apolipoprotein A1 Promotes Potent Anti-tumorigenic Effects

2013 ◽  
Vol 288 (29) ◽  
pp. 21237-21252 ◽  
Author(s):  
Maryam Zamanian-Daryoush ◽  
Daniel Lindner ◽  
Thomas C. Tallant ◽  
Zeneng Wang ◽  
Jennifer Buffa ◽  
...  
Keyword(s):  
Tumor Growth ◽  
Tumor Cells ◽  
Density Lipoprotein ◽  
Tumor Formation ◽  
Tumor Rejection ◽  
Apolipoprotein A1 ◽  
Major Protein ◽  
Tumor Growth And Metastasis

Here, we show that apolipoprotein A1 (apoA1), the major protein component of high density lipoprotein (HDL), through both innate and adaptive immune processes, potently suppresses tumor growth and metastasis in multiple animal tumor models, including the aggressive B16F10L murine malignant melanoma model. Mice expressing the human apoA1 transgene (A1Tg) exhibited increased infiltration of CD11b+ F4/80+ macrophages with M1, anti-tumor phenotype, reduced tumor burden and metastasis, and enhanced survival. In contrast, apoA1-deficient (A1KO) mice showed markedly heightened tumor growth and reduced survival. Injection of human apoA1 into A1KO mice inoculated with tumor cells remarkably reduced both tumor growth and metastasis, enhanced survival, and promoted regression of both tumor and metastasis burden when administered following palpable tumor formation and metastasis development. Studies with apolipoprotein A2 revealed the anti-cancer therapeutic effect was specific to apoA1. In vitro studies ruled out substantial direct suppressive effects by apoA1 or HDL on tumor cells. Animal models defective in different aspects of immunity revealed both innate and adaptive arms of immunity contribute to complete apoA1 anti-tumor activity. This study reveals a potent immunomodulatory role for apoA1 in the tumor microenvironment, altering tumor-associated macrophages from a pro-tumor M2 to an anti-tumor M1 phenotype. Use of apoA1 to redirect in vivo elicited tumor-infiltrating macrophages toward tumor rejection may hold benefit as a potential cancer therapeutic.

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