Post-Sepsis State Induces Tumor-Associated Macrophage Accumulation through CXCR4/CXCL12 and Favors Tumor Progression in Mice

Mota, José Maurício; Leite, Caio A.; Souza, Lucas Eduardo Botelho de; Melo, Paulo H.; Nascimento, Daniele C.; Wagatsuma, Virginia Mara De Deus; Temporal, Jessica; Figueiredo, Florêncio; Noushmehr, Houtan; Alves‐Filho, José C.; Cunha, Fernando; Rego, Eduardo Magalhães

doi:10.1158/2326-6066.cir-15-0170

Cited by 53 publications

(46 citation statements)

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“…In a mouse model of lung cancer, CXCL12 could recruit tumor-promoting myeloid CD11b+ cells [19]. Besides, powerful evidences indicate a role for CXCR4-CXCL12 axis in promoting macrophages polarization toward the M2 phenotype [37, 38]. In addition, M2 subpopulation is associated with angiogenic factors such as VEGF and CXCL12-CXCR4 axis can also promote tumor vascularization [39].…”

Section: Discussionmentioning

confidence: 99%

Targeting Tumor Microenvironment: Effects of Chinese Herbal Formulae on Macrophage‐Mediated Lung Cancer in Mice

Cui

Zhao

et al. 2017

Evidence-Based Complementary and Alternative Medicine

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Our previous studies have shown that Qing-Re-Huo-Xue (QRHX) formulae had significant anti-inflammatory effects in chronic airway diseases such as asthma and chronic obstructive lung disease. Here, we examined the effects of QRHX on lung cancer cell invasion and the potential associated mechanism(s), mainly polarization of macrophages in the tumor microenvironment. In vivo, QRHX both inhibited tumor growth and decreased the number of tumor-associated macrophages (TAMs) in mice with lung cancer. Further study indicated that QRHX inhibited cancer-related inflammation in tumor by decreasing infiltration of TAMs and IL-6 and TNF-α production and meanwhile decreased arginase 1 (Arg-1) expression and increased inducible NO synthase (iNOS) expression. QRHX could markedly inhibit CD31 and VEGF protein expression. Additionally, CXCL12/CXCR4 expression and JAK2/STAT3 phosphorylation were reduced in QRHX treatment group. Thus, we draw that QRHX played a more important role in inhibiting tumor growth by regulating TAMs in mice, which was found to be associated with the inhibition of inflammation and the CXCL12/CXCR4/JAK2/STAT3 signaling pathway.

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Section: Discussionmentioning

confidence: 99%

Targeting Tumor Microenvironment: Effects of Chinese Herbal Formulae on Macrophage‐Mediated Lung Cancer in Mice

Cui

Zhao

et al. 2017

Evidence-Based Complementary and Alternative Medicine

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“…There are no data that rigorously define the duration of immunoparalysis following a septic event, but recent data suggest it lasts at least for 60 days (in mice) as CLP surgery resulted in mice being more susceptible to tumor growth and development (179). To independently determine the duration of chronic immunoparalysis that increases tumor-associated mortality in sepsis survivors, B6 mice were challenged with B16 tumors at multiple times distal to surgery and subsequent cancer progression was monitored ( Figure 27A).…”

Section: Resultsmentioning

confidence: 99%

“…Use of the B16 tumor model disclosed unique immunological lesions specific to malignancy-bearing hosts including the rapid loss of highly-activated PD-1 hi CD8 TILs that occurred exclusively in the tumor environment. Since sepsis globally alters immune cell subsets, it could be predicted the increased tumor progression seen after sepsis is attributed to altered functionality of several cell subsets in the tumor, some of which have been explored previously (179,230). Despite this, it seems remarkable a targeted immunotherapy that inhibits ligation of activation/inhibitory receptors (PD-1 and LAG-3) on CD8 T cells appeared to completely negate the sepsis-induced impairments in tumor control when administered before the loss of PD-1 hi CD8 TILs was observed.…”

Section: Discussionmentioning

confidence: 99%

“…Cancer burden has been shown to impact a large frequency of human patients after sepsis induction, but mouse models may be a better method for addressing specific questions concerning the influence of sepsis on cancer progression (178). In mice, the immunoparalysis phase of sepsis has been shown to increase the frequency and immunosuppressive functions of TREG and TAMs that could provide a cellular source for diminished CD8 TIL responses (118,179). Considering this, it is surprising how limited our knowledge is on the capacity of sepsis survivors to mount efficacious antitumor CD8 T cell responses that may dramatically influence cancer outcome.…”

Section: Tumor Infiltrating Cd8 T Cellsmentioning

confidence: 99%

“…The limited amount of data shows increased tumor progression weeks/months after sepsis induction suggesting potential lesions in anti-tumor immune responses (179,230).…”

Section: Global Immune System Paralysis (Immunoparalysis) Is a Sequelmentioning

confidence: 99%

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Polymicrobial sepsis influences CD8 T cell responses and alters host susceptibility to infection and cancer

Danahy¹

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Thesis Supervisor: Associate Professor Vladimir P. Badovinac ii ACKNOWLEDGEMENTS I'd like to thank my mentor Vladimir Badovinac for allowing me to join his lab and be in a group of scientists that I'm proud to be a part of. Performing graduate work in Vladimir's lab has been a great experience and I thank him for fostering my scientific career. I'd like to recognize the Immunology Graduate Program at Iowa for providing curriculum, financial support, and opportunities to connect with my fellow students. Thanks to past and present lab members for their support during my graduate career with special emphasis on Matt Martin, Isaac Jensen, Christina Winborn, and Robert Strother all of whom significantly contributed to my overall happiness. Roger Berton and Steven Moioffer recently joined us, and I am confident they will develop into successful scientists and maintain the atmosphere that makes the Badovinac lab unique. Thank you to my thesis committee for the valuable feedback on my research projects. Additionally, I'd like to thank the many research collaborators that we worked with over the years that are too numerous to list. Lastly, I recognize my parents David and Johanna Danahy for their love and support.iii ABSTRACT Sepsis occurs when infection enters the circulation resulting in harmful or lethal levels of pro-and anti-inflammatory cytokines that affects nearly 2 million people in the U.S. annually. Improved identification and treatment options have increased survival of patients shortly after sepsis. However, this management of sepsis subsequently revealed survivors have increased long-term mortality rates due to altered immune responses that increase susceptibility to secondary complications. My thesis further revealed how sepsis impacts CD8 T cell-mediated immunity that protects the host against sepsis unrelated complications that will be useful for improving the outcome of sepsis survivors.Using vaccinia virus (VacV) to generate circulating (TCIRCM) and skin resident (TRM) memory CD8 T cells, I showed sepsis preferentially diminishes the number and function of TCIRCM, while TRM in barrier tissues were unaffected in mice that received a low-severity model of sepsis. Despite optimal number and 'sensing and alarming' function of skin TRM, the capacity of these cells to promote a tissue-wide recall response was lost after sepsis that increased viral burden upon homologous skin infection.Decreased sensitivity of vascular endothelium to TRM-derived IFN-γ was the underlying mechanism that diminished localized recall responses after sepsis. Overall, my data stress the importance of understanding how sepsis-induced lesions in T cell-extrinsic factors contribute to diminished T cell-mediated immunity observed after sepsis.Sepsis influence on T cell-mediated immunity has previously been explored using model pathogens. However, sepsis survivors are susceptible to an array of secondary complications, including cancer, which often occurs in patients with no previous history of malignancy. This suggested the immunoparalys...

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Tumor‐associated macrophages: A sentinel of innate immune system in tumor microenvironment gone haywire

Malik,

Sureka,

Ahuja

et al. 2024

Cell Biology International

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The tumor microenvironment (TME) is a critical determinant in the initiation, progression, and treatment outcomes of various cancers. Comprising of cancer‐associated fibroblasts (CAF), immune cells, blood vessels, and signaling molecules, the TME is often likened to the soil supporting the seed (tumor). Among its constituents, tumor‐associated macrophages (TAMs) play a pivotal role, exhibiting a dual nature as both promoters and inhibitors of tumor growth. This review explores the intricate relationship between TAMs and the TME, emphasizing their diverse functions, from phagocytosis and tissue repair to modulating immune responses. The plasticity of TAMs is highlighted, showcasing their ability to adopt either protumorigenic or anti‐tumorigenic phenotypes based on environmental cues. In the context of cancer, TAMs' pro‐tumorigenic activities include promoting angiogenesis, inhibiting immune responses, and fostering metastasis. The manuscript delves into therapeutic strategies targeting TAMs, emphasizing the challenges faced in depleting or inhibiting TAMs due to their multifaceted roles. The focus shifts towards reprogramming TAMs to an anti‐tumorigenic M1‐like phenotype, exploring interventions such as interferons, immune checkpoint inhibitors, and small molecule modulators. Noteworthy advancements include the use of CSF1R inhibitors, CD40 agonists, and CD47 blockade, demonstrating promising results in preclinical and clinical settings. A significant section is dedicated to Chimeric Antigen Receptor (CAR) technology in macrophages (CAR‐M cells). While CAR‐T cells have shown success in hematological malignancies, their efficacy in solid tumors has been limited. CAR‐M cells, engineered to infiltrate solid tumors, are presented as a potential breakthrough, with a focus on their development, challenges, and promising outcomes. The manuscript concludes with the exploration of third‐generation CAR‐M technology, offering insight into in‐vivo reprogramming and nonviral vector approaches. In conclusion, understanding the complex and dynamic role of TAMs in cancer is crucial for developing effective therapeutic strategies. While early‐stage TAM‐targeted therapies show promise, further extensive research and larger clinical trials are warranted to optimize their targeting and improve overall cancer treatment outcomes.

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Post-Sepsis State Induces Tumor-Associated Macrophage Accumulation through CXCR4/CXCL12 and Favors Tumor Progression in Mice

Cited by 53 publications

References 53 publications

Targeting Tumor Microenvironment: Effects of Chinese Herbal Formulae on Macrophage‐Mediated Lung Cancer in Mice

Targeting Tumor Microenvironment: Effects of Chinese Herbal Formulae on Macrophage‐Mediated Lung Cancer in Mice

Polymicrobial sepsis influences CD8 T cell responses and alters host susceptibility to infection and cancer

Tumor‐associated macrophages: A sentinel of innate immune system in tumor microenvironment gone haywire

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