The Hidden Battle Between Tumors and Your Immune System

By: Lara Lommers

The battle between the immune system and cancerous cells can be described as a war between cells in the human body. On one side of the battlefield are the cells that were once normal building blocks of the human body, but at some point mutated and started to grow rapidly. We call those cells tumor cells. On the other side are cytotoxic T lymphocytes (CTLs), which are specialized immune cells that can kill tumor cells with their effector molecules. While you might not notice it, a silent war arises between these cells inside the human body. What are they fighting over? Nutrients, especially cholesterol.

Over the years, tumors have developed ways to overcome the immune system and many existing immunotherapies. This growing resistance increases the need for innovative cancer treatments that enhance already existing immunotherapies¹. An enzyme inhibitor that targets cholesterol pathways, called Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) inhibitors, creates a promising area of investigation by potentially reviving CTL functions and boosting anti-tumor immunity^2,3.

Cholesterol: Not Just a Villain

You probably know cholesterol as a poor nutrient source that causes clogged arteries and heart disease. However, cholesterol is essential for maintaining cell functions, particularly in generating and maintaining cellular membranes^4,5. Both CTLs and tumor cells have a high demand for cholesterol, which they meet either by producing it themselves or by taking it up from their environment⁶. Since cholesterol is a lipid that does not mix well with water, it needs a carrier in the bloodstream to get to the cells that need it. Therefore, cholesterol is bound by low-density lipoprotein (LDL) in the blood, forming a complex better known as ‘bad’ cholesterol. The LDL complex can be taken up by cells through its receptor⁷. Once inside the cell, the LDL receptor dissociates from cholesterol, which can then be used for cellular processes. The LDL receptor is recycled back to the cell surface for further LDL uptake⁸.

CTLs get activated and start multiplying when they detect the presence of tumor cells, and therefore require more cellular membrane and more cholesterol uptake. Moreover, CTLs require cholesterol to maintain their function for hunting down and attacking tumor cells⁹. On the opposite side of the battle, tumor cells are also rapidly multiplying cells, causing an even higher need for cholesterol uptake. However, there is only so much cholesterol to go around. Being present together in the same environment, a war unfolds between tumor cells and CTLs for cholesterol uptake^10,11,12. Although, this does not seem to be a fair fight. Tumor cells make use of tricks to take up more cholesterol, effectively starving CTLs in the process, a tactic that benefits the tumor’s survival.

PCSK9: Tumor’s Secret Weapon

To win the nutrient war, tumor cells use a secret weapon: PCSK9¹². In the healthy human body, PCSK9 is produced by liver cells and is essential in the regulation of cholesterol levels in the blood. However, tumor cells have found a way to use it as a weapon to gain an advantage over CTLs. They produce PCSK9 and secrete it into the environment. PCSK9 can induce conformational changes to the LDL receptor, causing its degradation, instead of the receptor being recycled back to the surface. As a result of the increased degradation of the LDL receptor, the LDL uptake of the cell is impaired⁷. PCSK9 affects both tumor cells and CTLs. However, the ability of tumor cells to replicate quickly gives them an advantage compared to CTLs,  as they can adapt to their environment faster. Therefore, they can induce their cholesterol production and adapt to take up cholesterol from the environment in innovative ways^13,14. By using these tactics, tumor cells ensure their victory. Meanwhile, CTLs are left struggling. The crucial role of PCSK9 in this fight makes it a promising target for new therapies.

A New Hope with PCSK9 Inhibitors

The discovery of PCSK9 inhibitors gives new hope to the CTLs. These inhibitors bind to PCSK9 specifically and prevent them from binding to LDL receptors, allowing CTLs to take up more cholesterol from the bloodstream^2,3. PCSK9 inhibitors are already used in the clinic to treat diseases related to high levels of LDL (‘’bad cholesterol’’), such as heart and vascular diseases³. However, we can use this technology in our nutrient battle, giving back the upper hand to CTLs in their fight against the tumor cells.

Immunotherapies, such as PCSK9 inhibitors, have revolutionized cancer treatment by re-activating the body’s immune system to target and kill cancer cells. However, some cancers get resistant to certain immunotherapies, resulting in a need for new treatments. PCSK9 inhibitors are a promising additional approach to existing immunotherapies. An example where the combination appears to work well is with an immunotherapy for a surface protein on the CTLs, called PD. Cancer cells often exploit this surface protein to inactivate CTLs. PD inhibitors can block this pathway, which results in CTLs that can better recognize and kill cancer cells^1,15. Preclinical mice studies propose that combining PCSK9 inhibitors with other immunotherapies, particularly PD inhibitors, causes stronger anti-tumor effects and overcomes resistant tumor cells. PCSK9 inhibitors can increase the CTL infiltration into the tumor tissue, as well as boost the activity of CTLs, leading to a stronger immune response^2,3.

Despite these promising findings, this research is still in its early stages and much remains unknown about the effectiveness of PCSK9 inhibitors. Existing data mostly focuses on animal studies and more research needs to be done to understand the effects in humans. However, the literature and existing research suggest PCSK9 inhibitors to be an effective boost to existing immunotherapies, potentially leading to better outcomes in cancer patients.

Turning the Tide of Battle

The war for cholesterol between tumor cells and CTLs is one tumor cells have learned to manipulate to their advantage. By secreting PCSK9 to diminish cholesterol uptake by CTLs, tumor cells starve these immune cells and can grow without the interference of the immune system. However, researchers are finding a way to turn the tide of battle and give back the advantage to the immune system. Targeting metabolic pathways such as cholesterol uptake could be a novel therapeutic against certain types of cancer by reviving exhausted CTLs and ensuring enough nutrients for effector functions. The victory of CTLs may soon be within reach.

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Further reading

1.  Bao R, Hutson A, Madabhushi A, Jonsson VD, Rosario SR, Barnholtz-Sloan JS, et al. Ten challenges and opportunities in computational immuno-oncology. J Immunother Cancer. 2024 Oct 26;12(10):e009721. ↩︎
2. Yang QC, Wang S, Liu YT, Song A, Wu ZZ, Wan SC, et al. Targeting PCSK9 reduces cancer cell stemness and enhances antitumor immunity in head and neck cancer. iScience. 2023 Jun;26(6):106916. ↩︎
3. Wang R, Liu H, He P, An D, Guo X, Zhang X, et al. Inhibition of PCSK9 enhances the antitumor effect of PD-1 inhibitor in colorectal cancer by promoting the infiltration of CD8+ T cells and the exclusion of Treg cells. Front Immunol. 2022 Aug 8;13. ↩︎
4. Luo J, Yang H, Song BL. Mechanisms and regulation of cholesterol homeostasis. Nat Rev Mol Cell Biol. 2020 Apr 17;21(4):225–45. ↩︎
5. Yang ST, Kreutzberger AJB, Lee J, Kiessling V, Tamm LK. The role of cholesterol in membrane fusion. Chem Phys Lipids. 2016 Sep;199:136–43. ↩︎
6. Huang B, Song B liang, Xu C. Cholesterol metabolism in cancer: mechanisms and therapeutic opportunities. Nat Metab. 2020 Feb 10;2(2):132–41. ↩︎
7. Yuan J, Cai T, Zheng X, Ren Y, Qi J, Lu X, et al. Potentiating CD8+ T cell antitumor activity by inhibiting PCSK9 to promote LDLR-mediated TCR recycling and signaling. Protein Cell. 2021 Apr;12(4):240–60. ↩︎
8. Go GW, Mani A. Low-density lipoprotein receptor (LDLR) family orchestrates cholesterol homeostasis. Yale J Biol Med. 2012 Mar;85(1):19–28. ↩︎
9. Bonacina F, Moregola A, Svecla M, Coe D, Uboldi P, Fraire S, et al. The low-density lipoprotein receptor–mTORC1 axis coordinates CD8+ T cell activation. Journal of Cell Biology. 2022 Nov 7;221(11). ↩︎
10. Seidah NG, Prat A. The Multifaceted Biology of PCSK9. Endocr Rev. 2022 May 12;43(3):558–82. ↩︎
11. Bhattacharya A, Chowdhury A, Chaudhury K, Shukla PC. Proprotein convertase subtilisin/kexin type 9 (PCSK9): A potential multifaceted player in cancer. Biochimica et Biophysica Acta (BBA) – Reviews on Cancer. 2021 Aug;1876(1):188581. ↩︎
12. Ito M, Hiwasa T, Oshima Y, Yajima S, Suzuki T, Nanami T, et al. Association of Serum Anti-PCSK9 Antibody Levels with Favorable Postoperative Prognosis in Esophageal Cancer. Front Oncol. 2021 Aug 24;11. ↩︎
13. Guerra B, Recio C, Aranda-Tavío H, Guerra-Rodríguez M, García-Castellano JM, Fernández-Pérez L. The Mevalonate Pathway, a Metabolic Target in Cancer Therapy. Front Oncol. 2021 Feb 25;11. ↩︎
14. Juarez D, Fruman DA. Targeting the Mevalonate Pathway in Cancer. Trends Cancer. 2021 Jun;7(6):525–40. ↩︎
15. Wu J, Wang N. Current progress of anti‑PD‑1/PDL1 immunotherapy for glioblastoma (Review). Mol Med Rep. 2024 Sep 30;30(6):221. ↩︎