Innate Immune Defense Mechanisms by Myeloid Cells That Hamper Cancer Immunotherapy

Lebegge, Els; Arnouk, Sana M.; Bardet, Pauline M. R.; Kiss, Máté; Raes, Geert; Ginderachter, Jo A. Van

doi:10.3389/fimmu.2020.01395

Cited by 14 publications

(9 citation statements)

References 152 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Nowadays, it is well accepted that complement is a complex innate immune surveillance system, playing a key role in host homeostasis, inflammation, and defense [ 37 ]. In the tumor microenvironment, complement factors can perform nocanonical functions [ 23 ], such as stimulation of angiogenesis, inflammation, proliferation and migration, and they can even attenuate immunotherapy [ 25 , 67 ]. The therapeutic inhibition of complement components for cancer treatment has been well described [ 26 ], and the angogenesis-stimulating role of complements advocates the concept of applying mEHT in combination with angiogenesis inhibitors like Bevacizumab, which has been demonstrated to be beneficial for patients [ 4 ].…”

Section: Discussionmentioning

confidence: 99%

Modulated Electro-Hyperthermia Induces a Prominent Local Stress Response and Growth Inhibition in Mouse Breast Cancer Isografts

Schvarcz

Danics

Krenács

et al. 2021

Cancers

View full text Add to dashboard Cite

Modulated electro-hyperthermia (mEHT) is a selective cancer treatment used in human oncology complementing other therapies. During mEHT, a focused electromagnetic field (EMF) is generated within the tumor inducing cell death by thermal and nonthermal effects. Here we investigated molecular changes elicited by mEHT using multiplex methods in an aggressive, therapy-resistant triple negative breast cancer (TNBC) model. 4T1/4T07 isografts inoculated orthotopically into female BALB/c mice were treated with mEHT three to five times. mEHT induced the upregulation of the stress-related Hsp70 and cleaved caspase-3 proteins, resulting in effective inhibition of tumor growth and proliferation. Several acute stress response proteins, including protease inhibitors, coagulation and heat shock factors, and complement family members, were among the most upregulated treatment-related genes/proteins as revealed by next-generation sequencing (NGS), Nanostring and mass spectrometry (MS). pathway analysis demonstrated that several of these proteins belong to the response to stimulus pathway. Cell culture treatments confirmed that the source of these proteins was the tumor cells. The heat-shock factor inhibitor KRIBB11 reduced mEHT-induced complement factor 4 (C4) mRNA increase. In conclusion, mEHT monotherapy induced tumor growth inhibition and a complex stress response. Inhibition of this stress response is likely to enhance the effectiveness of mEHT and other cancer treatments.

show abstract

Section: Discussionmentioning

confidence: 99%

Modulated Electro-Hyperthermia Induces a Prominent Local Stress Response and Growth Inhibition in Mouse Breast Cancer Isografts

Schvarcz

Danics

Krenács

et al. 2021

Cancers

View full text Add to dashboard Cite

show abstract

“…A substantial amount of preclinical and clinical studies has indicated that tumor-associated myeloid cells, predominantly tumorassociated macrophages (TAMs), neutrophils, and myeloidderived suppressor cells (MDSCs), sustain an immunosuppressive tumor microenvironment, which is particularly refractory to both T cell trafficking and antitumor T cell functions (4,(129)(130)(131)(132)(133)(134). Extensive research in this field has additionally concluded that the specific targeting and/or elimination of this myeloid-driven immunosuppressive program can render the natural, induced, and engineered immunological responses against tumors more concrete and effective (135)(136)(137). In line with the above, here we first provide proof-of-principle evidence of this notion using the Mouse Mammary Tumor Virus Polyoma Middle-T antigen (MMTV-PyMT) mouse model of breast carcinoma, which successfully recapitulates human breast cancer progression (138).…”

Section: The Cancer Cell Dissemination Trajectory As An Immunosuppresmentioning

confidence: 99%

“…In recent years, the molecular/cellular investigation of the immune tumor microenvironment and the comprehensive studying of the immunosuppressive mechanisms harbored therein have been at the frontier of cancer research, as an attempt to improve the already promising landscape of cancer immunotherapy (1,86,132,135,151). In this regard, we offer a fresh perspective on the topic by distinguishing disparate sets of immunosuppressive mechanisms in different tumor microenvironments.…”

Section: Conclusion and Future Perspectivesmentioning

confidence: 99%

The Cancer Cell Dissemination Machinery as an Immunosuppressive Niche: A New Obstacle Towards the Era of Cancer Immunotherapy

et al. 2021

View full text Add to dashboard Cite

Although cancer immunotherapy has resulted in unpreceded survival benefits to subsets of oncology patients, accumulating evidence from preclinical animal models suggests that the immunosuppressive tumor microenvironment remains a detrimental factor limiting benefit for many patient subgroups. Recent efforts on lymphocyte-mediated immunotherapies are primarily focused on eliminating cancer foci at primary and metastatic sites, but few studies have investigated the impact of these therapies on the highly complex process of cancer cell dissemination. The metastatic cascade involves the directional streaming of invasive/migratory tumor cells toward specialized blood vessel intravasation gateways, called TMEM doorways, to the peripheral circulation. Importantly, this process occurs under the auspices of a specialized tumor microenvironment, herewith referred to as “Dissemination Trajectory”, which is supported by an ample array of tumor-associated macrophages (TAMs), skewed towards an M2-like polarization spectrum, and which is also vital for providing microenvironmental cues for cancer cell invasion, migration and stemness. Based on pre-existing evidence from preclinical animal models, this article outlines the hypothesis that dissemination trajectories do not only support the metastatic cascade, but also embody immunosuppressive niches, capable of providing transient and localized immunosubversion cues to the migratory/invasive cancer cell subpopulation while in the act of departing from a primary tumor. So long as these dissemination trajectories function as “immune deserts”, the migratory tumor cell subpopulation remains efficient in evading immunological destruction and seeding metastatic sites, despite administration of cancer immunotherapy and/or other cytotoxic treatments. A deeper understanding of the molecular and cellular composition, as well as the signaling circuitries governing the function of these dissemination trajectories will further our overall understanding on TAM-mediated immunosuppression and will be paramount for the development of new therapeutic strategies for the advancement of optimal cancer chemotherapies, immunotherapies, and targeted therapies.

show abstract

“…However, tumor cells also develop mechanisms to evade immune surveillance and could mold myeloid cells to serve the tumor. Functionally, tumor-associated myeloid cells are often divided into anti- or pro-tumor subgroups [ 9 , 10 , 11 ]. The anti-tumoral group are associated with immunostimulatory cells with the secretion of pro-inflammatory cytokines (e.g TNF-α, IL-12, and IL-6).…”

Section: Introductionmentioning

confidence: 99%

Zebrafish Xenograft Model for Studying Pancreatic Cancer-Instructed Innate Immune Microenvironment

Wang

Jiang

et al. 2022

IJMS

View full text Add to dashboard Cite

Pancreatic ductal adenocarcinoma (PDAC) has up to half the tumor mass of tumor-associated myeloid cells. Myeloid innate immune cells play important roles in regulating cancer cell recognition and tumor growth. PDAC cells often mold myeloid cells into pro-tumoral state to fuel cancer growth and induce immune suppression. However, how tumor cells educate the innate immune responses remains largely unknown. In this study, we used four different human PDAC cell lines (PANC1, BxPC3, AsPC1, and CFPAC1) to establish the zebrafish xenograft model and investigated the interaction between pancreatic cancer and innate immune cells. The primary tumor-derived cancer cells PANC1 and BxPC3 activated innate immune anti-tumoral responses efficiently, while cancer cells from metastatic tissues AsPC1 and CFPAC1 induced an innate immune suppression and educated innate immune cells towards pro-tumoral state. Chemical conversion of innate immune cells to anti-tumoral state inhibited tumor growth for AsPC1 and CFPAC1. Moreover, genetic and pharmacological inhibition of macrophages also significantly reduced tumor growth, supporting the important roles of macrophages in innate immune suppression. REG4 expression is high in AsPC1 and CFPAC1. Knockdown of REG4 induced innate immune activation and reduced tumor growth in the xenografts, indicating that REG4 is a beneficial target for PDAC therapy. Our study provides a fast in-vivo model to study PDAC-innate immune interaction and their plasticity that could be used to study the related mechanism as well as identify new drugs to enhance immunotherapy.

show abstract

Innate Immune Defense Mechanisms by Myeloid Cells That Hamper Cancer Immunotherapy

Cited by 14 publications

References 152 publications

Modulated Electro-Hyperthermia Induces a Prominent Local Stress Response and Growth Inhibition in Mouse Breast Cancer Isografts

Modulated Electro-Hyperthermia Induces a Prominent Local Stress Response and Growth Inhibition in Mouse Breast Cancer Isografts

The Cancer Cell Dissemination Machinery as an Immunosuppressive Niche: A New Obstacle Towards the Era of Cancer Immunotherapy

Zebrafish Xenograft Model for Studying Pancreatic Cancer-Instructed Innate Immune Microenvironment

Contact Info

Product

Resources

About