How activated dendritic cells can boost the immune system and fight diseases

How activated dendritic cells can boost the immune system and fight diseases

By Evangelia Vogiatzaki

What are dendritic cells?

Dendritic cells (DCs) are an important part of the immune system, which coordinate between different types of immune responses. These responses can be:

  • Innate, involving non-specific defense mechanisms that come into play immediately or within hours of an antigen’s appearance in the body.
  • Adaptive, involving a complex, antigen-specific response and a “memory” that allows for more efficient future responses.

 

Scientists are now able to harness DCs to attack multiple pieces of a complex cancer simultaneously. Therapies based on DCs such as cancer vaccines have the potential to create large, sustained immune responses against cancer, and could become an important aspect of personalized immunotherapies.

The role of DCs in our immune system:

DCs (also known as accessory cells) process and present soluble antigens, in complex with either class I or class II major histocompatibility complex (MHC) molecules on their cell surface, to the B or T cells, which carry receptor molecules that recognize specific targets. DCs thus act as messengers between the innate immune system and the adaptive immune system.

DCs are present in trace numbers in most tissues and in a relatively immature state, especially in the blood. However, in the presence of inflammatory signals, they rapidly recognize foreign antigens and undergo maturation. Once activated, they migrate to the lymph nodes, where they interact with T and B cells to initiate an immune response.

How are DCs activated?

Dendritic cell activation can occur in two ways:

  • Directly by conserved pathogen molecules.
  • Indirectly by inflammatory mediators (which are produced by other cell types that recognize such molecules), cellular stress molecules, or disturbances in the internal body environment.

 

It is possible that these different activation pathways have evolved to ensure the early detection of infections before invading pathogens replicate in overwhelming numbers.

What are the latest scientific advancements of DCs?

Currently, it is possible to proliferate populations of DCs in vitro from various cellular sources including bone marrow, umbilical cord blood, and peripheral blood. Following appropriate stimulation, T cells can proliferate extensively in vitro. Traditionally, mitogenic lectins such as phytohemagglutinin (PHA) and concanavalin A (Con A) have been used for polyclonal T cell stimulation. Nowadays, beads coated with anti-CD3 and anti-CD28 are used to stimulate T cells in a manner that partially mimics stimulation by antigen-presenting cells.

This has shed light on the developmental biology of DCs and improved our knowledge of the mechanisms of antigen processing and presentation, which has ultimately led to improved strategies for vaccination and immunotherapy.

How does activated DC technology work?

Novel technologies are using activated DCs designed to regenerate and educate the immune system to attack cancer profiles. Cancer is a complex and variable disease; tumor profiles vary among patients with the same type of cancer, and cancer cells change their proliferation strategies after being treated with different drugs. Unlike conventional cancer drugs, which use a single active agent to attack a single target on the cancer cells, therapies based on activated DCs aim to use many active molecules that target different components of a cancer cell.

Usually, a sample that contains antigens of a patient with cancer is collected and used to produce activated autologous DCs, programmed to target these specific antigens. These activated, antigen-loaded DCs are then fused with the patient’s plasma, and administered via intradermal injection as a personalized immunotherapy.

Advantages of activated DCs:

Once in the patient’s body, these activated dendritic cells can mobilize a number of different biomarkers in a patient’s tumor profile (including antibodies, T cells, particular interleukins, and interferons). Dendritic cell-based immunotherapy is safe and can induce anti-tumor immunity, even in patients with advanced disease. Clinical studies and scientific research have shown that in some cases, this treatment has slowed disease progression or extended patient’s survival over standard drug treatments.

DC-based vaccines: A promising alternative for cancer treatment?

Findings from emerging research indicate that DC-based vaccination might also improve survival of cancer patients. Vaccination is one of the most effective methods to prevent many diseases. Preventive vaccines induce specific antibodies and long-lived memory B cells, but they can also induce cellular immunity. As mentioned above, DCs play a central role in the orchestration of immune responses, and are thus key targets in cancer vaccine design.

In contrast to chemotherapy, DC-based vaccines do not have a direct anti-tumor activity, but aim to reinvigorate patients’ immune systems in order to achieve this goal. In addition, they can generate long-lived memory CD8+ T cells that will act to prevent relapse.

As mentioned in the review of K. Palucka and J. Banchereau (2013), DCs can be exploited for vaccination against cancer through various means including:

  1. Non-targeted peptide/protein and nucleic acids-based vaccines captured by DCs in vivo.
  2. Vaccines composed of antigens directly coupled to anti-DC antibodies.
  3. Vaccines composed of ex vivo generated DCs that are loaded with antigens.

 

The FDA approved the first DC-based cancer vaccine (Sipuleucel-T, trade name Provenge) in 2010. Since that time, scientific advancements have made the design of DC-based vaccines more efficient and there has been increasing interest in exploiting these cells as a therapeutic option for the treatment of tumors of diverse origin.  

Many clinical trials using DC-based vaccines have shown them to be feasible—able to elicit immunological responses with few side effects. However, recent reviews that discuss the clinical effects of DC-based vaccines highlight the major difference observed between the immunogenicity and the therapeutic efficacy in terms of inducing tumor rejection. This clinical challenge emphasizes the importance and the need for further research.

Future prospects:

Therapies based on activated DCs are a promising tool for personalized cancer treatments. They can mobilize large and sustained immune responses, and appear to be non-toxic.

However, the clinical benefit provided by DC-based vaccines is still limited, and the choice of the optimal antigen formulation remains an unresolved issue. One promising future approach could use polyvalent vaccines, which target distinct yet specific DC subsets, to trigger an ideal composite anti-cancer immune response. Improvements in patient selection, vaccine delivery strategies, immune monitoring, and vaccine manufacturing will be crucial in moving DC-based vaccines closer to reality for the treatment of cancer.

Featured image: By National Institutes of Health (NIH) – National Institutes of Health (NIH), Public Domain. It is an artistic rendering of the surface of a human dendritic cell illustrating sheet-like processes that fold back onto the membrane surface. When exposed to HIV, these sheets entrap viruses in the vicinity and focus them to contact zones with T-cells targeted for infection. These studies were carried out using ion abrasion scanning electron microscopy, a new technology we have been developing and applying for 3D cellular imaging.


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