This Cell Could Revolutionize Cancer Treatments

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Visionary Hub

10 min readFeb 2, 2022

Imagine a creature. This creature has a round base. Long tentacles extend from the base that are perfect for catching its prey.

The creature that you’re thinking of probably looks like this:

Octopi? Octopuses? The plural of octopus is a mystery for another day 🐙. Image credit: Unsplash

This creature does match my description. An octopus does have long tentacles attached to its round base (in this case, the head) that it uses to eat clams and sea snails.

Surprise! This is not the creature that I was describing. And no, it isn’t a squid either.

I’m thinking of a dendritic cell.

Okay, they do look a bit weird, but I promise that they’re really important. Image credit: Biology Dictionary

Dendritic cells make up some of the approximately 37.2 trillion cells in your body. But they’re still able to stand out from the crowd. Why? Not only are they the main antigen-presenting cells in the body, but they could be the next step in cancer treatments.

In this article, I’m going to cover the basics of dendritic cells, some different types of dendritic cells, and which of those types would be the most effective vaccine for cancer.

So let’s start with the groundwork!

Psst… if you’re feeling lazy, scroll to the bottom for a TL;DR section!

Dendritic Cells 101

Dendritic cells (DCs) are a type of leukocyte, aka white blood cells. They are part of your body’s first line of defence (the innate immune system) against any potentially harmful microorganisms, known as pathogens.

The job of the DCs is to take the remains of pathogens (called antigens) and present them to the adaptive immune system if a situation gets out of hand. The adaptive immune system is your body’s second line of defence and has more specific weaponry against pathogens.

In short, dendritic cells are like Gordon Ramsay in a heated episode of Hell’s Kitchen🔥. They run the show and have the power to call for reinforcements if needed.

If a DC feels the need to call in the adaptive immune system, it will take its samples and use the lymph vessels to get to a lymph node. Lymph nodes are like a big Starbucks where DCs meet inactivated T cells and B cells. In the lymph node, the DC will start looking for a T cell that it will have to activate.

So how do dendritic cells activate other cells?

DCs have a special tool available to them because of their status as professional antigen-presenting cells (APCs). They have special molecules called MHC (major histocompatibility complex)-II that function as a window, showing off the antigen samples that the DC collected. The DC would extend the antigen to a naïve T cell with receptors that bind with the antigen samples. Once the DC finds a compatible T cell, it will extend the antigen towards the naïve T cell. In turn, the T cell will reach out and touch the antigen.

This is called antigen cross-presentation. In a nutshell, the T cell will become activated and be ready to join the innate immune system to fight the pathogens.

Let’s break this down a bit more with an analogy.

Imagine you were out for a relaxing walk. You turn the corner, and there it is: the bear. It’s giving you a death stare and you suddenly become very aware that you’re within 2 metres of it. As it begins snarling and menacingly walking towards you, your instinct (if it isn’t to run) is to brace yourself for battle.

So what does this have to do with anything? Well, the bear triggers your fight or flight response (for the sake of this analogy, let’s go with fight 🗡). This is how T cells react to antigens. But since cells can’t see, their response is triggered with touch.

A diagram showing the process of a DC activating a CD4+ T cell. Image credit: Nature

Types of Dendritic Cells

There are a few main types of DCs, so I’m only going to cover the ones that are relevant to this article.

Conventional type 1 dendritic cells (cDC1s) excel at cross-presenting antigens, particularly in vivo (inside a living organism). cDC1s aren’t the only DCs that can cross-present antigens; cDC2s (conventional type 2 DCs) and pDCs (plasmacytoid DCs) also possess this ability. However, cDC1s have been proven to outperform cDC2s when presenting soluble or particulate antigens with the help of Toll-like receptor (TLR) ligands. cDC1s also produce high levels of IL-12 and IL-15. This helps with the activation of Natural Killer (NK) cells and Natural Killer T (NKT) cells. For this article, we’re going to focus on a subset of cDC1s: XCR1+.

A diagram comparing cDC1s and cDC2s. IL stands for interleukin, Tregs are T regulatory cells, Th1 is Type 1 Helper Cells, Th2 is Type 2 Helper Cells, and Tfh stands for Thyroid Follicular Hypertrophy. Image credit: Science Direct

CD1c+ dendritic cells are a subset of cDC2s. cDC2s produce CD4+ T cells that promote anti-tumor immunity. CD1c+ cells specifically are known for their knack at activating CD4+ T cells. They are also efficient at MHC-II antigen presentation in addition to their ability to present antigens to CD8+ T cells. However, it’s still unknown what exactly they do in the body.

Plasmacytoid dendritic cells (pDCs) are typically involved in encouraging the tolerance of innocuous/self-antigens. pDCs are known for their impact on anti-viral immunity and their production of type 1 interferons (IFN1). IFN1 can improve CD141+XCR1+ DCs’ cross-presentation, which leads to enhanced CD8+ T cell responses. pDCs are also able to match cDC1s’ antigen cross-presenting efficiency once activated by TLR7 ligands, despite having a lower antigen uptake capacity.

A diagram showing what pDCs can do and what effects it has on the body. Image credit: Nature

With all that background information out of the way, it’s time to decide what makes a good cancer vaccine.

Traits of an Effective DC Cancer Vaccine

Now, cancer vaccines using DCs have been made before using monocyte-derived dendritic cells (MoDCs). Was it a good vaccine? Not really.

Despite the high safety profile, there is still a problem with the MoDCs used for the cancer vaccines: they were generated in vitro (cultured in a lab). This lead to functional limitations, as the MoDCs were not in good shape. Only 15% of patients had a clear therapeutic outcome after taking the vaccine.

This is why researchers are looking for new types of DCs to use in vaccines. Here are some criteria that the optimal DC should follow:

Quality of vaccine-elicited CD8+ T cell immunity. CD8+ T cells are very important T cells. They consist of cytotoxic T cells and CD8-positive suppressor T cells. Cytotoxic T cells are important counters against cancer and CD8-positive suppressor T cells make sure that the immune system is attacking the enemy and not the innocent bystanders. Therefore, a prime DC vaccine should be able to evoke these T cells.
Quality of vaccine-elicited CD4+ T cells. Now, to have effective CD8+ T cells, you need to have effective CD4+ T cells. These cells can boost immune cells (including CD8+ T cells) and are generally responsible for immune cell regulation and anti-viral immunity. Some CD4+ T cells (specifically Th1s, or Type 1 T helper cells) can release IFNy, which can signal for CD8+ T cells.
Barriers that vaccine-elicited CD8+ T cells must confront to access and reject cancer. It’s no use if we have perfect CD8+ T cells, only for a T regulatory cell (Treg) to come along and kill it because it looked a bit suspicious. Additionally, the CD8+ T cells must deal with a new tumor microenvironment, changes in surrounding tissues, and even antigen loss. This has been the subject of many clinical studies, but a possible solution is the combination of DCs and regulatory agents (ex. immune checkpoint inhibitors).

Now that we have our criteria set, it’s time to put all the contending DCs against each other and see which one could be the next cancer vaccine.

What is the Optimal DC for Cancer Vaccines?

I’m going to be comparing results of clinical trials and research that have experimented with cDC1s as a whole, CD1c+, XCR1+, and pDCs. I will also see if these results abide by the criteria laid out above and point out any other faults with the DCs.

cDC1s

cDC1s fulfill the criteria listed above. They are the prime APCs for activating CD8+ T cells. They can also activate CD4+ T cells using MHC class I molecules.

It’s believed that if cDC1s were to be used as a vaccine, combining it with immune checkpoint inhibitors could make the treatment stronger. Another benefit is the Flt3L molecule. Using this molecule, cDC1s can be led to the site of the tumor.

However, pure cDC1s aren’t very common in the body. Additionally, current trials are primarily using cancer cells genetically modified to express XCL1 (a type of cytokine responsible for intracellular calcium within lymphocytes).

A diagram showing the different ways that cDC1s could potentially be used as a vaccine. Image credit: NCBI

CD1c+

CD1c+ cells fill the second of our criteria exceptionally well. After all, it’s their “claim to fame”. Unfortunately, CD1c+ cells don’t activate CD8+ T cells.

Studies using purified CD1c+ cells proved that DC vaccines were safe to use. A trial used primary circulating CD1c+ cells in 14 patients with stage IV melanoma cancer. 4 out of these 14 patients had strong T cell activation and anti-tumor responses. This was followed up with a 12–35 month period with progression-free survival.

CD1c+ cells are also one of the larger DC subsets that can be found in the body, eliminating the problem that cDC1s have. Because of the ambiguity of these cells, there are still some hypothetical issues if they were to be used as a cancer vaccine.

XCR1+

XCR1+ cells are important players when it comes to adaptive immune responses against viral infections and in CD8+ T cell immunity. Interestingly enough, they can be used to assist existing cancer treatments such as chemotherapy and radiotherapy. This is because they can trigger anti-cancer immunity in response to these treatments. Finally, XCR1+ cells are sufficient in activating CTLs (cytotoxic T lymphocytes).

On the other hand, XCR1+ doesn’t fill out all of the criteria as it doesn’t activate CD4+ T cells. This problem is solved if the CTLs that they activate are CD4 CTLs. Additionally, stress from a total mesorectal excision (TME), which is a surgical procedure related to cancer, can affect antigen cross-presentation in some DCs (including XCR1+).

All in all, there are still a lot of gaps in the usage of XCR1+. Scientists need to improve the migration, activation, function, and maturation of these cells.

pDCs

The production of IFN1 in pDCs already checks off the first criteria because, again, IFN1 assists CD8+ T cell responses. In addition to this, certain metastatic melanoma patients who have been injected with pDCs (equipped with tumor antigen-peptides) showed both CD8+ and CD4+ antigen-specific responses.

On the downside, in a study where nine patients were given pDC vaccines, all nine of them reported having some sort of adversary event (AE). This varied from nausea to bronchitis (when the lining of the bronchial tubes becomes inflamed). A total of 20 severe AEs between eight patients occurred during the study.

Because patients had received previous treatments, the study was inconclusive when evaluating the potential clinical benefits of their vaccine. There were also no humoral or cellular allogeneic responses that came with using pDCs.

Conclusion

All these DCs show potential due to their unprecedented ability to cross-present antigens and activate CD4+ T cells and CD8+ T cells. But after comparison, it’s clear that cDC1s as a whole would be the most effective cancer vaccine.

cDC1s have the lowest risk factor if they were to be used as a vaccine. Even if they are in low supply, scientists can use stem cells (baby cells that can mature into any type of cell in the body) to develop more DCs.

cDC1s are also the best at their job, outperforming all other DCs in antigen cross-presentation.

Finally, there is more information on cDC1s as a whole compared to some of the other DCs covered in this article (looking at you, CD1c+).

Because of those reasons, cDC1 beats out CD1+, XCR1+, and pDCs to take the crown as the best DC to be used as a cancer vaccine 🏆

TL;DR

Dendritic cells (DCs) are leaders in the innate immune system (your body’s first line of defence against any invading microorganisms). Their job is to collect samples and present them to the adaptive immune system (your body’s second line of defence) if needed.
To present these samples (known as antigens), the DCs use molecules called MHC (major histocompatibility complex)-II. The process of presenting these antigens to a T cell is called antigen cross-presentation.
There are a few types of DCs, some of which are cDC1s, CD1c+, XCR1+, and pDCs.
The criteria for having a good DC vaccine are the quality of vaccine-elicited CD8+ T cell immunity, quality of vaccine-elicited CD4+ T cells, and barriers that vaccine-elicited CD8+ T cells must confront to access and reject cancer.
The most effective DC to be used as a vaccine are cDC1s because of their top-notch ability to cross-present antigens and the lowest risk factor out of all the other DCs.