The Evolution of Dendritic Cell Immunotherapy against HIV-1 Infection: Improvements and Outlook

Dendritic cells (DC) are key phagocytic cells that play crucial roles in both the innate and adaptive immune responses against the human immunodeficiency virus type 1 (HIV-1). By processing and presenting pathogen-derived antigens, dendritic cells initiate a directed response against infected cells. They activate the adaptive immune system upon recognition of pathogen-associated molecular patterns (PAMPs) on infected cells. During the course of HIV-1 infection, a successful adaptive (cytotoxic CD8+ T-cell) response is necessary for preventing the progression and spread of infection in a variety of cells. Dendritic cells have thus been recognized as a valuable tool in the development of immunotherapeutic approaches and vaccines effective against HIV-1. The advancements in dendritic cell vaccines in cancers have paved the way for applications of this form of immunotherapy to HIV-1 infection. Clinical trials with patients infected with HIV-1 who are well-suppressed by antiretroviral therapy (ART) were recently performed to assess the efficacy of DC vaccines, with the goal of mounting an HIV-1 antigen-specific T-cell response, ideally to clear infection and eliminate the need for long-term ART. This review summarizes and compares methods and efficacies of a number of DC vaccine trials utilizing autologous dendritic cells loaded with HIV-1 antigens. The potential for advancement and novel strategies of improving efficacy of this type of immunotherapy is also discussed.

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Dendritic cells loaded with apoptotic tumour cells induce a stronger T-cell response than dendritic cell–tumour hybrids in B-CLL

Leukemia ◽

10.1038/sj.leu.2402913 ◽

2003 ◽

Vol 17 (5) ◽

pp. 894-899 ◽

Cited By ~ 51

Author(s):

P Kokhaei ◽

M R Rezvany ◽

L Virving ◽

A Choudhury ◽

H Rabbani ◽

...

Keyword(s):

Dendritic Cells ◽

T Cell ◽

Dendritic Cell ◽

Cell Response ◽

Tumour Cells ◽

T Cell Response ◽

Cell Tumour

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Human Cytomegalovirus (HCMV)-Specific CD4+ T Cells Are Polyfunctional and Can Respond to HCMV-Infected Dendritic Cells In Vitro

Journal of Virology ◽

10.1128/jvi.02128-16 ◽

2017 ◽

Vol 91 (6) ◽

Cited By ~ 28

Author(s):

Sarah E. Jackson ◽

George X. Sedikides ◽

Gavin M. Mason ◽

Georgina Okecha ◽

Mark R. Wills

Keyword(s):

T Cells ◽

Dendritic Cells ◽

T Cell ◽

Human Cytomegalovirus ◽

Immune Cells ◽

Cell Response ◽

T Cell Response ◽

Cell Responses ◽

Infected Cells

ABSTRACT Human cytomegalovirus (HCMV) infection and periodic reactivation are generally well controlled by the HCMV-specific T cell response in healthy people. While the CD8+ T cell response to HCMV has been extensively studied, the HCMV-specific CD4+ T cell effector response is not as well understood, especially in the context of direct interactions with HCMV-infected cells. We screened the gamma interferon (IFN-γ) and interleukin-10 (IL-10) responses to 6 HCMV peptide pools (pp65, pp71, IE1, IE2, gB, and US3, selected because they were the peptides most frequently responded to in our previous studies) in 84 donors aged 23 to 74 years. The HCMV-specific CD4+ T cell response to pp65, IE1, IE2, and gB was predominantly Th1 biased, with neither the loss nor the accumulation of these responses occurring with increasing age. A larger proportion of donors produced an IL-10 response to pp71 and US3, but the IFN-γ response was still dominant. CD4+ T cells specific to the HCMV proteins studied were predominantly effector memory cells and produced both cytotoxic (CD107a expression) and cytokine (macrophage inflammatory protein 1β secretion) effector responses. Importantly, when we measured the CD4+ T cell response to cytomegalovirus (CMV)-infected dendritic cells in vitro, we observed that the CD4+ T cells produced a range of cytotoxic and secretory effector functions, despite the presence of CMV-encoded immune evasion molecules. CD4+ T cell responses to HCMV-infected dendritic cells were sufficient to control the dissemination of virus in an in vitro assay. Together, the results show that HCMV-specific CD4+ T cell responses, even those from elderly individuals, are highly functional and are directly antiviral. IMPORTANCE Human cytomegalovirus (HCMV) infection is carried for a lifetime and in healthy people is kept under control by the immune system. HCMV has evolved many mechanisms to evade the immune response, possibly explaining why the virus is never eliminated during the host's lifetime. The dysfunction of immune cells associated with the long-term carriage of HCMV has been linked with poor responses to new pathogens and vaccines when people are older. In this study, we investigated the response of a subset of immune cells (CD4+ T cells) to HCMV proteins in healthy donors of all ages, and we demonstrate that the functionality of CD4+ T cells is maintained. We also show that CD4+ T cells produce effector functions in response to HCMV-infected cells and can prevent virus spread. Our work demonstrates that these HCMV-specific immune cells retain many important functions and help to prevent deleterious HCMV disease in healthy older people.

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Functional Role of Dendritic Cell Subsets in Cancer Progression and Clinical Implications

International Journal of Molecular Sciences ◽

10.3390/ijms21113930 ◽

2020 ◽

Vol 21 (11) ◽

pp. 3930

Author(s):

Annalisa Del Prete ◽

Francesca Sozio ◽

Ilaria Barbazza ◽

Valentina Salvi ◽

Laura Tiberio ◽

...

Keyword(s):

Dendritic Cells ◽

T Cell ◽

Dendritic Cell ◽

Cancer Progression ◽

Cell Response ◽

Functional Role ◽

T Cell Response ◽

Cytotoxic T Cell ◽

Dendritic Cell Subsets

Dendritic cells (DCs) constitute a complex network of cell subsets with common functions but also with many divergent aspects. All dendritic cell subsets share the ability to prime T cell response and to undergo a complex trafficking program related to their stage of maturation and function. For these reasons, dendritic cells are implicated in a large variety of both protective and detrimental immune responses, including a crucial role in promoting anti-tumor responses. Although cDC1s are the most potent subset in tumor antigen cross-presentation, they are not sufficient to induce full-strength anti-tumor cytotoxic T cell response and need close interaction and cooperativity with the other dendritic cell subsets, namely cDC2s and pDCs. This review will take into consideration different aspects of DC biology, including the functional role of dendritic cell subsets in both fostering and suppressing tumor growth, the mechanisms underlying their recruitment into the tumor microenvironment, as well as the prognostic value and the potentiality of dendritic cell therapeutic targeting. Understanding the specificity of dendritic cell subsets will allow to gain insights on role of these cells in pathological conditions and to design new selective promising therapeutic approaches.

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Optimal CD8 T-Cell Response against Encephalitozoon cuniculi Is Mediated by Toll-Like Receptor 4 Upregulation by Dendritic Cells

Infection and Immunity ◽

10.1128/iai.00181-10 ◽

2010 ◽

Vol 78 (7) ◽

pp. 3097-3102 ◽

Cited By ~ 18

Author(s):

Elizabeth M. Lawlor ◽

Magali M. Moretto ◽

Imtiaz A. Khan

Keyword(s):

Dendritic Cells ◽

T Cell ◽

Dendritic Cell ◽

Cell Response ◽

T Cell Response ◽

T Cell Immunity ◽

Toll Like Receptor ◽

Encephalitozoon Cuniculi ◽

Toll Like Receptor 4 ◽

Cell Immunity

ABSTRACT CD8+ T-cell immunity has been shown to play an important role in the protective immune response against Encephalitozoon cuniculi. Although earlier studies suggest that dendritic cells (DC) are important for the induction of this response, the factors responsible for initiation of the dendritic cell response against this pathogen have not been evaluated. In the current study, we demonstrate that E. cuniculi infection causes strong Toll-like receptor 4 (TLR4)-dependent dendritic cell activation and a blockade of this molecule reduces the ability of DC to prime an antigen-specific CD8+ T-cell response. Pretreatment of DC with anti-TLR4 antibody causes a defect in both in vitro and in vivo CD8+ T-cell priming. These findings, for the first time, emphasize the contribution of TLR4 in the induction of CD8+ T-cell immunity against E. cuniculi infection.

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Faculty Opinions recommendation of Dendritic cells maximize the memory CD8 T cell response to infection.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1025997.321895 ◽

2005 ◽

Author(s):

David Woodland

Keyword(s):

Dendritic Cells ◽

T Cell ◽

Cell Response ◽

Cd8 T Cell ◽

T Cell Response ◽

Memory Cd8 T Cell

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Decreased expression of MHC class II and cathepsin E in dendritic cells might contribute to impaired induction of antigen-specific T cell response in NC/Nga mice

The Journal of Medical Investigation ◽

10.2152/jmi.59.95 ◽

2012 ◽

Vol 59 (1,2) ◽

pp. 95-101 ◽

Cited By ~ 1

Author(s):

Tohru Sakai ◽

Emi Shuto ◽

Tomoyo Taki ◽

Honami Imamura ◽

Miku Kioka ◽

...

Keyword(s):

Dendritic Cells ◽

T Cell ◽

Mhc Class Ii ◽

Cell Response ◽

Class Ii ◽

T Cell Response ◽

Cathepsin E

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Cellular Immune Response Induced by DNA Immunization of Mice with Drug Resistant Integrases of HIV-1 Clade A Offers Partial Protection against Growth and Metastatic Activity of Integrase-Expressing Adenocarcinoma Cells

Microorganisms ◽

10.3390/microorganisms9061219 ◽

2021 ◽

Vol 9 (6) ◽

pp. 1219

Author(s):

Maria Isaguliants ◽

Olga Krotova ◽

Stefan Petkov ◽

Juris Jansons ◽

Ekaterina Bayurova ◽

...

Keyword(s):

Oxidative Stress ◽

T Cell ◽

Cell Response ◽

Mammalian Cells ◽

Metastatic Potential ◽

T Cell Response ◽

Dna Immunization ◽

Drug Resistant ◽

Metastatic Activity ◽

Hiv 1

Therapeutic DNA-vaccination against drug-resistant HIV-1 may hinder emergence and spread of drug-resistant HIV-1, allowing for longer successful antiretroviral treatment (ART) up-to relief of ART. We designed DNA-vaccines against drug-resistant HIV-1 based on consensus clade A integrase (IN) resistant to raltegravir: IN_in_r1 (L74M/E92Q/V151I/N155H/G163R) or IN_in_r2 (E138K/G140S/Q148K) carrying D64V abrogating IN activity. INs, overexpressed in mammalian cells from synthetic genes, were assessed for stability, route of proteolytic degradation, and ability to induce oxidative stress. Both were found safe in immunotoxicity tests in mice, with no inherent carcinogenicity: their expression did not enhance tumorigenic or metastatic potential of adenocarcinoma 4T1 cells. DNA-immunization of mice with INs induced potent multicytokine T-cell response mainly against aa 209–239, and moderate IgG response cross-recognizing diverse IN variants. DNA-immunization with IN_in_r1 protected 60% of mice from challenge with 4Tlluc2 cells expressing non-mutated IN, while DNA-immunization with IN_in_r2 protected only 20% of mice, although tumor cells expressed IN matching the immunogen. Tumor size inversely correlated with IN-specific IFN-γ/IL-2 T-cell response. IN-expressing tumors displayed compromised metastatic activity restricted to lungs with reduced metastases size. Protective potential of IN immunogens relied on their immunogenicity for CD8+ T-cells, dependent on proteasomal processing and low level of oxidative stress.

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Dendritic cells support a proliferative antigen‐specific T‐cell response in the presence of poly(lactic‐co‐glycolic acid)

Journal of Biomedical Materials Research Part A ◽

10.1002/jbm.a.37211 ◽

2021 ◽

Author(s):

Sangeetha Srinivasan ◽

Julia Babensee

Keyword(s):

Dendritic Cells ◽

T Cell ◽

Cell Response ◽

Glycolic Acid ◽

T Cell Response

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Targeting cancer-associated fibroblast-secreted WNT2 restores dendritic cell-mediated antitumour immunity

Gut ◽

10.1136/gutjnl-2020-322924 ◽

2021 ◽

pp. gutjnl-2020-322924

Author(s):

Tuxiong Huang ◽

Xiang-Yu Tan ◽

Hui-Si Huang ◽

Yu-Ting Li ◽

Bei-Lei Liu ◽

...

Keyword(s):

T Cell ◽

Dendritic Cell ◽

Cell Response ◽

T Cell Responses ◽

Tumour Microenvironment ◽

T Cell Response ◽

Cell Responses ◽

Cancer Associated Fibroblast ◽

Anticancer Immunotherapy ◽

Novel Therapeutic Strategies

ObjectiveSolid tumours respond poorly to immune checkpoint inhibitor (ICI) therapies. One major therapeutic obstacle is the immunosuppressive tumour microenvironment (TME). Cancer-associated fibroblasts (CAFs) are a key component of the TME and negatively regulate antitumour T-cell response. Here, we aimed to uncover the mechanism underlying CAFs-mediated tumour immune evasion and to develop novel therapeutic strategies targeting CAFs for enhancing ICI efficacy in oesophageal squamous cell carcinoma (OSCC) and colorectal cancer (CRC).DesignAnti-WNT2 monoclonal antibody (mAb) was used to treat immunocompetent C57BL/6 mice bearing subcutaneously grafted mEC25 or CMT93 alone or combined with anti-programmed cell death protein 1 (PD-1), and the antitumour efficiency and immune response were assessed. CAFs-induced suppression of dendritic cell (DC)-differentiation and DC-mediated antitumour immunity were analysed by interfering with CAFs-derived WNT2, either by anti-WNT2 mAb or with short hairpin RNA-mediated knockdown. The molecular mechanism underlying CAFs-induced DC suppression was further explored by RNA-sequencing and western blot analyses.ResultsA negative correlation between WNT2+ CAFs and active CD8+ T cells was detected in primary OSCC tumours. Anti-WNT2 mAb significantly restored antitumour T-cell responses within tumours and enhanced the efficacy of anti-PD-1 by increasing active DC in both mouse OSCC and CRC syngeneic tumour models. Directly interfering with CAFs-derived WNT2 restored DC differentiation and DC-mediated antitumour T-cell responses. Mechanistic analyses further demonstrated that CAFs-secreted WNT2 suppresses the DC-mediated antitumour T-cell response via the SOCS3/p-JAK2/p-STAT3 signalling cascades.ConclusionsCAFs could suppress antitumour immunity through WNT2 secretion. Targeting WNT2 might enhance the ICI efficacy and represent a new anticancer immunotherapy.

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