Immune Cells in Cancer Therapy and Drug Delivery

Recent studies indicate the critical role of tumour associated macrophages, tumour associated neutrophils, dendritic cells, T lymphocytes, and natural killer cells in tumourigenesis. These cells can have a significant impact on the tumour microenvironment via their production of cytokines and chemokines. Additionally, products secreted from all these cells have defined specific roles in regulating tumour cell proliferation, angiogenesis, and metastasis. They act in a protumour capacityin vivoas evidenced by the recent studies indicating that macrophages, T cells, and neutrophils may be manipulated to exhibit cytotoxic activity against tumours. Therefore therapy targeting these cells may be promising, or they may constitute drug or anticancer particles delivery systems to the tumours. Herein, we discussed all these possibilities that may be used in cancer treatment.

Download Full-text

WDFY4 is required for cross-presentation in response to viral and tumor antigens

Science ◽

10.1126/science.aat5030 ◽

2018 ◽

Vol 362 (6415) ◽

pp. 694-699 ◽

Cited By ~ 69

Author(s):

Derek J. Theisen ◽

Jesse T. Davidson ◽

Carlos G. Briseño ◽

Marco Gargaro ◽

Elvin J. Lauron ◽

...

Keyword(s):

T Cells ◽

Dendritic Cells ◽

Tumor Antigens ◽

Critical Role ◽

Tumor Rejection ◽

Interleukin 12 ◽

Cross Presentation ◽

Histocompatibility Complex ◽

Crispr Screen

During the process of cross-presentation, viral or tumor-derived antigens are presented to CD8+ T cells by Batf3-dependent CD8α+/XCR1+ classical dendritic cells (cDC1s). We designed a functional CRISPR screen for previously unknown regulators of cross-presentation, and identified the BEACH domain–containing protein WDFY4 as essential for cross-presentation of cell-associated antigens by cDC1s in mice. However, WDFY4 was not required for major histocompatibility complex class II presentation, nor for cross-presentation by monocyte-derived dendritic cells. In contrast to Batf3–/– mice, Wdfy4–/– mice displayed normal lymphoid and nonlymphoid cDC1 populations that produce interleukin-12 and protect against Toxoplasma gondii infection. However, similar to Batf3–/– mice, Wdfy4–/– mice failed to prime virus-specific CD8+ T cells in vivo or induce tumor rejection, revealing a critical role for cross-presentation in antiviral and antitumor immunity.

Download Full-text

In Vivo Role of Dendritic Cells in a Murine Model of Pulmonary Cryptococcosis

Infection and Immunity ◽

10.1128/iai.00317-06 ◽

2006 ◽

Vol 74 (7) ◽

pp. 3817-3824 ◽

Cited By ~ 58

Author(s):

Karen L. Wozniak ◽

Jatin M. Vyas ◽

Stuart M. Levitz

Keyword(s):

T Cells ◽

Dendritic Cells ◽

T Cell Activation ◽

Cell Activation ◽

Ex Vivo ◽

Interleukin 2 ◽

Mouse Lung

ABSTRACT Dendritic cells (DC) have been shown to phagocytose and kill Cryptococcus neoformans in vitro and are believed to be important for inducing protective immunity against this organism. Exposure to C. neoformans occurs mainly by inhalation, and in this study we examined the in vivo interactions of C. neoformans with DC in the lung. Fluorescently labeled live C. neoformans and heat-killed C. neoformans were administered intranasally to C57BL/6 mice. At specific times postinoculation, mice were sacrificed, and lungs were removed. Single-cell suspensions of lung cells were prepared, stained, and analyzed by microscopy and flow cytometry. Within 2 h postinoculation, fluorescently labeled C. neoformans had been internalized by DC, macrophages, and neutrophils in the mouse lung. Additionally, lung DC from mice infected for 7 days showed increased expression of the maturation markers CD80, CD86, and major histocompatibility complex class II. Finally, ex vivo incubation of lung DC from infected mice with Cryptococcus-specific T cells resulted in increased interleukin-2 production compared to the production by DC from naïve mice, suggesting that there was antigen-specific T-cell activation. This study demonstrated that DC in the lung are capable of phagocytosing Cryptococcus in vivo and presenting antigen to C. neoformans-specific T cells ex vivo, suggesting that these cells have roles in innate and adaptive pulmonary defenses against cryptococcosis.

Download Full-text

Correlation Between Immune Lymphoid Cells and Plasmacytoid Dendritic Cells in Human Colon Cancer

10.21203/rs.3.rs-46781/v1 ◽

2020 ◽

Author(s):

Jing Wu ◽

Hang Cheng ◽

Tete Li ◽

Helei Wang ◽

Guoxia Zang ◽

...

Keyword(s):

Colon Cancer ◽

Dendritic Cells ◽

Rna Sequencing ◽

Immune Cells ◽

Human Colon ◽

Tumour Microenvironment ◽

Plasmacytoid Dendritic Cells ◽

Lymphoid Cells ◽

Human Colon Cancer

Abstract Background: Innate lymphoid cells (ILCs), so far studied mostly in mouse models, are important tissue-resident innate immune cells that play important roles in the colorectal cancer microenvironment and maintain the mucosal tissue homeostasis. Plasmacytoid dendritic cells (pDCs) present complexity in various tumour types and are correlated with poor prognosis. pDCs can promote HIV-1–induced group 3 ILC (ILC3) depletion through the CD95 pathway. However, the role of ILC3s in human colon cancer and their correlation with other immune cells, especially pDCs, remain unclear. Methods: We characterised ILCs and pDCs in the tumour microenvironment of 58 colon cancer patients by flow cytometry and selected three patients for RNA sequencing. Results: ILC3s were negatively correlated, and pDCs were positively correlated, with cancer pathological grade. There was a negative correlation between the numbers of ILC3s and pDCs in tumour tissues. RNA sequencing confirmed the correlations between ILC3s and pDCs and highlighted the potential function of many ILC- and pDC-associated differentially expressed genes in the regulation of tumour immunity. pDCs can induce apoptosis of ILC3s through the CD95 pathway in the tumour microenvironment. Conclusions: One of the interactions between ILC3s and pDCs is via the CD95 pathway, which may help explain the role of ILC3s in colon cancer.

Download Full-text

The role of the tumour microenvironment in the angiogenesis of pituitary tumours

Endocrine ◽

10.1007/s12020-020-02478-z ◽

2020 ◽

Vol 70 (3) ◽

pp. 593-606

Author(s):

Pedro Marques ◽

Sayka Barry ◽

Eivind Carlsen ◽

David Collier ◽

Amy Ronaldson ◽

...

Keyword(s):

T Cells ◽

B Cells ◽

Immune Cells ◽

Microvessel Density ◽

Tumour Microenvironment ◽

Vascular Morphology ◽

Hla Dr ◽

M1 Macrophage ◽

Culture Supernatants

Abstract Purpose Angiogenesis has been studied in pituitary neuroendocrine tumours (PitNETs), but the role of the tumour microenvironment (TME) in regulating PitNET angiogenesis remains unknown. We aimed to characterise the role of TME components in determining the angiogenetic PitNET profile, focusing on immune cells and tumour-derived cytokines. Methods Immune cells were studied by immunohistochemistry in 24 human PitNETs (16 non-functioning-PitNETs (NF-PitNETs) and 8 somatotrophinomas): macrophages (CD68, CD163, HLA-DR), cytotoxic (CD8) and T helper (CD4) lymphocytes, regulatory T cells (FOXP3), B cells (CD20) and neutrophils (neutrophil elastase); endothelial cells were assessed with CD31. Five normal pituitaries (NP) were included for comparison. Microvessel density and vascular morphology were estimated with ImageJ. The cytokine secretome from these PitNETs were assessed on culture supernatants using a multiplex immunoassay panel. Results Microvessel density/area was higher in NP than PitNETs, which also had rounder and more regular vessels. NF-PitNETs had vessels of increased calibre compared to somatotrophinomas. The M2:M1 macrophage ratio correlated with microvessel area. PitNETs with more CD4+ T cells had higher microvessel area, while tumours with more FOXP3+ cells were associated with lower microvessel density. PitNETs with more B cells had rounder vessels. Of the 42 PitNET-derived cytokines studied, CCL2, CXCL10 and CX3CL1 correlated with microvessel density and vessel architecture parameters. Conclusions M2 macrophages appear to play a role in PitNET neovascularisation, while B, CD4+ and FOXP3+ lymphocytes, as well as non-cellular TME elements such as CCL2, CXCL10 and CX3CL1, may also modulate the angiogenesis of PitNETs.

Download Full-text

Allogeneic Environment and Tissue Damage Provide Critical Stimuli for Regulatory T Cell Expansion and Survival In Vivo after Hematopoietic Cell Transplantation.

Blood ◽

10.1182/blood.v108.11.1731.1731 ◽

2006 ◽

Vol 108 (11) ◽

pp. 1731-1731

Author(s):

Vu H. Nguyen ◽

Daisy Chang ◽

Robert S. Negrin

Keyword(s):

Bone Marrow ◽

T Cells ◽

Tissue Damage ◽

Hematopoietic Cell Transplantation ◽

Critical Role ◽

Lymphoid Organs ◽

Gamma Chain ◽

Secondary Lymphoid Organs

Abstract CD4+CD25+ regulatory T cells (Treg) mediate alloresponses in murine models of bone marrow transplantation (BMT), leading to protection from graft-versus-host disease (GvHD). However, in vivo migration and tissue localization of Treg during this inflammatory response remain unclear. We previously demonstrated co-localization of Treg with effector T cells (Tcon) with initial expansion in secondary lymphoid organs prior to migration into inflamed tissues in a major MHC-mismatched BMT model. To explore the stimuli for Treg proliferation, we evaluated the role of the allogeneic environment by transferring FVB donor luciferase-expressing (luc+) Treg into lethally-irradiated syngeneic recipients. Unlike the allogeneic irradiated setting where Treg expand in the presence or absence of Tcon, adoptively transferred luc+ Treg were not detected in secondary lymphoid organs of syngeneic lethally-irradiated BMT recipients by in vivo bioluminescence imaging (BLI). Syngeneic luc+ Tcon also had significantly different in vivo dynamics, with a 4 day delay and only moderate expansion in lymph nodes. Proliferation was not detected in the spleen, unlike their allogeneic Tcon counterparts, nor in the bone marrow compartments, as seen in lymphopenic models. To assess whether irradiation induced the observed in vivo dynamics of Treg in the allogeneic setting, we transferred FVB luc+ Treg or luc+ Tcon into unirradiated Balb/c Rag2−/−gamma chain (γC) −/− recipients, which lack T, B, and NK cells. After adoptive transfer into Rag2−/−γC−/− recipients, robust Tcon proliferation was observed in secondary lymphoid organs and the bone marrow compartments; however, Treg expansion was weak, and specific localization to lymphoid or nonlymphoid tissues was not observed. Treg were stimulated to localize to and expand in secondary lymphoid organs by the co-transfer of Tcon in unirradiated Rag2−/− (γC) −/− or by conditioning Rag2−/− (γC) −/− recipients with irradiation. Exogenous IL2 administration two weeks following luc+ Treg transfer into unirradiated Rag2−/− (γC) −/− recipients similarly led to localization and expansion of Treg in secondary lymphoid organs. These studies indicate the critical role of proinflammatory cytokines, such as IL2, generated either by irradiation-induced tissue damage or donor Tcon, in the expansion and localization of Treg. Differences between Tcon and Treg expansion in syngeneic or unconditioned allogeneic Rag2−/− γC−/− hosts suggest an important role of conditioning with irradiation alone or in concert with the allogeneic environment, in providing distinct signals for Tcon versus Treg activation, proliferation, and localization.

Download Full-text

Calreticulin Promotes Immunity Against Acute Myeloid Leukemia Cells in Vivo

Blood ◽

10.1182/blood.v124.21.996.996 ◽

2014 ◽

Vol 124 (21) ◽

pp. 996-996

Author(s):

Xiufen Chen ◽

Dominick Fosco ◽

Douglas E. Kline ◽

Justin Kline

Keyword(s):

T Cells ◽

Dendritic Cells ◽

T Cell ◽

Cell Surface ◽

Vector Control ◽

Immune Cells ◽

Myeloid Leukemia ◽

Innate Immune ◽

Innate Immune Cells

Abstract Pre-apoptotic cancer cells release internalized calreticulin (CRT) to their surface prior to death, which acts as an ‘eat-me’ signal to local phagocytes. Chemotherapy and irradiation, which can induce immunogenic cell death through CRT translocation, can also result in local and/or systemic immune suppression in the host. To bypass the requirement of exposing the host to chemotherapy to induce translocation of CRT to the cell surface, murine acute myeloid leukemia (AML) cells (C1498), were engineered to constitutively express cell surface CRT (C1498.CRT). Vector control C1498 or C1498.CRT cells were inoculated intravenously (IV) into C57BL/6 mice. Significantly prolonged survival was observed in hosts harboring C1498.CRT versus vector control C1498 cells systemically. The survival benefit were abrogated in both Rag2-/- hosts or by depletion of T cells with anti-CD4 plus anti-CD8 antibodies, arguing that the immune-mediated effect of cell-surface CRT expression is dependent upon a functional adaptive immune system. More strikingly, systemic inoculation with C1498.CRT cells expressing the model SIYRYYGL (SIY) peptide antigen (C1498.SIY.CRT cells) resulted in almost complete protection from AML development (>90% long term survival vs. 10% of C1498.SIY vector control cells). All animals surviving a primary C1498.SIY.CRT challenge rejected a subsequent re-challenge with C1498.SIY cells, suggesting that CRT-expressing AML cells promote immunologic memory. Significantly enhanced expansion and unregulated IFNγ production were observed among SIY-specific T cell receptor transgenic CD8+ 2C T cells following their adoptive transfer into hosts bearing C1498.SIY.CRT AML cells versus vector control C1498.SIY cells. Interestingly, CRT expression on AML cells did not promote their in vivo phagocytosis by innate immune cells, specifically splenic CD8a+ dendritic cells known to engulf AML cells following their IV inoculation. IL-12 production by CD8α+CD11c+ dendritic cells which had engulfed C1498 and C1498.CRT cells in vivo was similarly induced, and cross-presentation of the SIY antigen to 2C T cells ex vivo by purified CD8a+DCs following in vivo exposure to C1498.SIY or C1498.SIY.CRT cells was also similar. In conclusion, it is clear that expression on CRT on the surface of AML cells leads to robust leukemia-specific T cell activation and expansion resulting in prolonged leukemia-specific survival in AML-bearing animals. Although a direct effect of CRT on innate immune cells, such as dendritic cells, is suspected, the molecular mechanism underlying the “CRT effect” remains unclear, and is being explored further through gene expression analysis in purified DCs which have engulfed CRT-expressing or control AML cells in vivo, as well as in animals genetically deficient in the putative CRT receptor, LRP, in dendritic cells. It will be of interest to analyze spontaneous CRT expression on AML cells from human samples and to correlate cell surface CRT expression with the presence or absence of spontaneous T cell responses to known AML antigens and with clinical outcomes. Disclosures No relevant conflicts of interest to declare.

Download Full-text

Interfering with MIF-CD74 signalling on macrophages and dendritic cells with a peptide-based approach restores the immune response against metastatic melanoma

10.1101/248807 ◽

2018 ◽

Author(s):

Carlos R. Figueiredo ◽

Ricardo A. Azevedo ◽

Sasha Mousdell ◽

Pedro T. Resende-Lara ◽

Lucy Ireland ◽

...

Keyword(s):

Immune Response ◽

Dendritic Cells ◽

Metastatic Melanoma ◽

Immune Cells ◽

Tumour Microenvironment ◽

Innate Immune ◽

Innate Immune Cells ◽

Adaptive Immune Cells ◽

Cancer Immunotherapies

ABSTRACTMounting an effective immune response against cancer requires the activation of innate and adaptive immune cells. Metastatic melanoma is the most aggressive form of skin cancer. Immunotherapies that boost the activity of effector T cells have shown a remarkable success in melanoma treatment. Patients, however, can develop resistance to such therapies by mechanisms that include the establishment of an immune suppressive tumour microenvironment. Understanding how metastatic melanoma cells suppress the immune system is vital to develop effective immunotherapies against this disease. In this study, we find that the innate immune cells, macrophages and dendritic cells are suppressed in metastatic melanoma. The Ig-CDR-based peptide C36L1 is able to restore macrophages and dendritic cells’ immunogenic functions and to inhibit metastatic growth in vivo. Mechanistically, we found that C36L1 interferes with the MIF-CD74 tumour-innate immune cells immunosuppressive signalling pathway and thereby restores an effective anti-tumour immune response. C36L1 directly binds to CD74 on macrophages and dendritic cells, disturbing CD74 structural dynamics and inhibiting MIF signalling through CD74. Our findings suggest that interfering with MIF-CD74 immunosuppressive signalling in macrophages and dendritic cells using peptide-based immunotherapy can restore the anti-tumour immune response in metastatic melanoma. Our study provides the rationale for further development of peptide-based therapies to restore the anti-tumour immune response.

Download Full-text

DUSP12 regulates the tumorigenesis and prognosis of hepatocellular carcinoma

PeerJ ◽

10.7717/peerj.11929 ◽

2021 ◽

Vol 9 ◽

pp. e11929

Author(s):

Gaoda Ju ◽

Tianhao Zhou ◽

Rui Zhang ◽

Xiaozao Pan ◽

Bing Xue ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

T Cells ◽

Immune Cells ◽

Malignant Tumors ◽

Critical Role ◽

Normal Liver ◽

Functional Enrichment ◽

Loss Of Function ◽

Liver Tissues

Background Dual specificity protein phosphatase (DUSP)12 is an atypical member of the protein tyrosine phosphatase family, which are overexpressed in multiple types of malignant tumors. This protein family protect cells from apoptosis and promotes the proliferation and motility of cells. However, the pathological role of DUSP12 in hepatocellular carcinoma (HCC) is incompletely understood. Methods We analyzed mRNA expression of DUSP12 between HCC and normal liver tissues using multiple online databases, and explored the status of DUSP12 mutants using the cBioPortal database. The correlation between DUSP12 expression and tumor-infiltrating immune cells was demonstrated using the Tumor Immune Estimation Resource database and the Tumor and Immune System Interaction Database. Loss of function assay was utilized to evaluate the role of DUSP12 in HCC progression. Results DUSP12 had higher expression along with mRNA amplification in HCC tissues compared with those in normal liver tissues, which suggested that higher DUSP12 expression predicted shorter overall survival. Analyses of functional enrichment of differentially expressed genes suggested that DUSP12 regulated HCC tumorigenesis, and that knockdown of DUSP12 expression by short hairpin (sh)RNA decreased the proliferation and migration of HCC cells. Besides, DUSP12 expression was positively associated with the infiltration of cluster of differentiation (CD)4+ T cells (especially CD4+ regulatory T cells), macrophages, neutrophils and dendritic cells. DUSP12 expression was positively associated with immune-checkpoint moieties, and was downregulated in a C3 immune-subgroup of HCC (which had the longest survival). Conclusion These data suggest that DUSP12 may have a critical role in the tumorigenesis, infiltration of immune cells, and prognosis of HCC.

Download Full-text