The Science behind “Cells at Work!!” Episode 7: “Cancer Cell II (Part I)”

In this episode, Neutrophil, NK Cell and Memory T Cell get trapped by Cancer Cell who takes them to his lair in the colon. They try to fight against Cancer Cell and his paper puppets, but Cancer Cell sends in Regulatory T Cell to defend him. Regulatory T Cell successfully fends off attacks from NK Cell and Memory T Cell, defeating them in the process. Meanwhile, Cancer Cell traps Neutrophil in a pod to question him about his existence. Following this, Cancer Cell evolves to become more dangerous, planning to kill the body to take the other cells with him.

This anime episode is a continuation to the Cancer Cell episode from season 1 which I covered in a previous blog post. In that blog post, I explained what cancer is and the features that cancer cells possess to endlessly proliferate and metastasise. In this blog post, I will talk about two more features that can further promote cancer growth and spread: the tumour microenvironment and immune escape. I will then talk about the role of regulatory T cells in promoting cancer growth and discuss how cancer treatments can enhance immune responses against cancer. 

Tumour microenvironment and its contribution to immune escape

In the episode, Cancer Cell manipulates his paper puppets to attack the white blood cells, controlling his environment to defend himself against the white blood cells. This describes what happens in the tumour microenvironment, the cellular environment inside a tumour that cancer cells can control to support their growth and metastasis. The tumour microenvironment consists of blood vessels, factors and cells that can promote the growth and development of cancer cells.

Within the tumour, blood vessels are often unorganised and leaky, resulting in an unequal distribution of oxygen within the tumour. Hence, there will be some hypoxic areas where no oxygen is delivered, altering the metabolism of cancer cells. Other areas; though, will be well-supplied with oxygen and factors from the blood to promote the cancer’s invasion into healthy tissue and metastasis into the blood. Inflammation is also present in the tumour microenvironment. Similar to what happens in wound healing, inflammation can promote blood vessel creation and cell proliferation, contributing to further cancer growth. Lastly, cancer cells can release factors to tune the tumour microenvironment to further promote cancer growth and metastasis. For example, cancer cells release a variety of factors to suppress immune responses such as TGF-β, IDO1 and adenosine. The suppression of immune responses which is required for immune cells to detect and eliminate cancer cells enables immune escape by cancer cells, allowing them to remain undetected as they continue to evolve, proliferate and develop and eventually cause relapse.

Cells in the tumour microenvironment also contribute to cancer growth and immune escape. The most common cells present in the tumour microenvironment are cancer-associated fibroblasts. They are fibroblasts that create structures within tissue, but they are directed by cancer cells to release factors that promote cancer growth and metastasis such as TGF-β to suppress immune responses and VEGF to create new blood vessels. Similarly, MDSCs (myeloid-derived suppressor cells) are immunosuppressive, immature myeloid cells inside tumours that promote the development of new blood vessels and inhibit immune responses. Lastly, M2 macrophages, being geared towards tissue repair and immunosuppression, contribute to cancer growth, particularly at the edge of the tumour to assist cancer cells to invade nearby healthy tissue. These cells, and many others in the tumour microenvironment, can create a tumour microenvironment where cancer cells can grow and develop unimpeded. There is one key cell in the tumour microenvironment; though, that is showcased in the anime episode, and that is what we will discuss next.  

The role of regulatory T cells in immune escape

In the episode, Regulatory T Cell served Cancer Cell well in defending him against Killer T Cell’s and NK Cell’s attacks, countering them in the process. In real-life, regulatory T cells are a big problem in cancer, residing in the tumour microenvironment to inhibit immune responses essential for detecting and eliminating cancer cells. In fact, having a high proportion of regulatory T cells in the tumour is associated with cancer relapse and reduced survival rates against cancer.

Regulatory T cells are derived from CD4⁺ T cells, the same predecessor cells that produce helper T cells. Regulatory T cells possess cell surface markers CD4 and CD25 which characterise CD4⁺ T cells as well as transcription factor FoxP3 to maintain their immunosuppressive function. They also have co-inhibitory molecules such as CTLA-4 and PD-1 that inhibit immune responses and chemokine receptors such as CCR4 and CXCR3 to migrate to tumours. Regulatory T cells have five ways to suppress immune responses and promote cancer growth:

1. Secreting immunosuppressive molecules: regulatory T cells can secrete immunosuppressive cytokines such as TGF-β, IL-10 and IL-35 to inhibit the proliferation, function and cytotoxicity of immune cells, suppressing immune activity against cancer cells. 
2. Cytotoxicity: regulatory T cells can kill killer T and NK cells by using the death receptor TRAIL to direct cells to die or releasing proteins such as granzyme B (which cuts up proteins inside killer T and NK cells) and galectin-1 (which binds to cell surface proteins on killer T and NK cells to impede their function). 
3. Metabolic disruption: regulatory T cells can deplete certain cytokines that are essential for maintaining immune responses. For instance, regulatory T cells use CD25 to consume IL-2 in the tumour microenvironment. This deprives helper and killer T cells of IL-2 which is essential for their survival and proliferation, leading to cell death. Regulatory T cells also use CD39 and CD73 to cleave extracellular AMP to adenosine which inhibits activation and proliferation of helper and killer T cells. 
4. Dendritic cell (DC) modulation: regulatory T cells can impede the ability of DCs to activate T cells. Regulatory T cells use CTLA-4 on their cell surface to bind to CD80 and CD86 on DCs. This blocks co-stimulation to prevent DCs from activating helper or killer T cells. Regulatory T cells also promote IDO1 production in DCs. IDO1 is an enzyme that converts tryptophan to kynurenine which have cytotoxic effects in DCs. 
5. Manipulating the tumour microenvironment: regulatory T cells can release cytokines to enhance the immunosuppressive activities of other cells in the tumour microenvironment. For instance, cancer-associated fibroblasts release chemokines such as CCL2 and CXCL12 to attract regulatory T cells to the tumour. In return, regulatory T cells produce TGF-β to turn more fibroblasts into cancer-associated fibroblasts and IL-10 to maintain the tumour microenvironment’s suppression of immune responses.

Taken together, regulatory T cells can play a major role in suppressing immune responses against cancer. This allows cancer cells to escape immune detection and activity to grow, proliferate and develop unimpeded which can contribute to cancer growth and metastasis. This makes regulatory T cells attractive targets to restore immune activity against cancer cells.

Immunotherapy

Cancer treatment normally consists of targeting cancer cells to prevent cancer growth and metastasis. However, targeting only cancer cells may exert selection pressure, where some cancer cells that are resistant to treatment survive, causing relapse in the future. Recent cancer treatments have focused on targeting parts of the tumour microenvironment, particularly cells, to restore immune responses against cancer. Immunotherapy harnesses the immune system or immunological products (such as monoclonal antibodies) to boost immune responses against cancer.

Checkpoint inhibitors are monoclonal antibodies that target cell surface molecules such as PD-1 and CTLA-4 on DCs and T cells, particularly regulatory T cells, to remove the inhibition of immune responses against cancer cells. Both antibodies are given intravenously, where they travel to the tumour to exert their actions. Anti-CTLA-4 antibodies (ipilimumab), which are commonly used to treat melanomas, bind to CTLA-4 on T cells. This binding prevents CTLA-4 from binding to co-stimulatory molecules CD80 and CD86 on DCs to suppress T cell responses, allowing CD80 and CD86 to provide co-stimulatory signals to inactive T cells. This allows helper T cells to promote immune responses and killer T cells to target and kill cancer cells. In contrast, anti-PD-1 antibodies (pembrolizumab and nivolumab) bind to PD-1 on T cells, preventing PD-1 from binding to its ligand PD-1L on cancer cells to suppress T cell responses. 

Both antibodies not only act on helper and killer T cells themselves to promote their immune functions, but they can also target and deplete regulatory T cells that express lots of CTLA-4 and PD-1, removing the suppression of immune responses against cancer. These antibodies are often combined with other cancer treatments such as chemotherapy and radiotherapy to reduce the risk that resistant cancer cells survive and proliferate, causing relapse in the future. 

Conclusion

This anime episode describes two more features of cancer: the tumour microenvironment and immune escape. The tumour microenvironment consists of many components that assist cancer cells in their growth and metastasis. One big part of the tumour microenvironment is immunosuppression provided by various cells such as regulatory T cells and factors such as IL-10. Immunosuppression contributes to immune escape, where cancer cells can escape detection and elimination to quietly proliferate and develop, setting themselves up for relapse in the future. A main focus of cancer treatment and research now is controlling the tumour microenvironment to enhance immune activity against cancer which is spearheaded by immunotherapy. It is hoped that further advances in immunotherapy will make it a viable cancer treatment that can be widely applied to cancer patients globally. 

In the next blog post, I will talk about the cancer where the episode takes place which is common globally and can be easily treated if detected early. See you then!

References

The most helpful reviews I found when learning more about the tumour microenvironment are Quail and Joyce’s 2013 review on Nature Medicine and Wang et al.’s 2018 review on European Review for Medical and Pharmacological Sciences. I used a few reviews to look at the role of regulatory T cells in cancer, including Najafi et al.’s 2019 review on the Journal of Cellular Physiology, Ward-Hartstonge and Kemp’s 2017 review on Clinical & Translational Immunology and Wing et al.’s 2019 review in Immunity.