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Cancer immunotherapy has been a very hot topic here at OncoBites (because it’s a hot topic right now among cancer researchers too), but let me be super clear ⎯ it is COMPLICATED. Your immune system is balanced extremely delicately to avoid sending you into shock each time you are exposed to bacteria, viruses, or other foreign proteins. However, we do not yet completely understand how cancer cells are able to upset this balance and use it for their own benefit. We know that tumors can influence how the immune system responds to cancer cells, but we only know some of the ways so far; that’s how we developed checkpoint inhibitors like Keytruda. Recently, scientists at the National Cancer Institute think they’ve found another way; the amount of potassium in a tumor might be starving immune cells and keeping them from actively fighting tumors.
Now, before you throw out your bananas, hold on. This is not diet related. Your bananas are not to blame. The facts are, unsurprisingly, more complicated. When cells die through a process called necrosis, they release their contents into their surrounding environment. Remember, cells don’t have hands, so they can’t reach out and grab what they need. Instead, they have developed a system of receptors and transporters that rely on a stable electrochemical gradient, which reliably maintains a concentration of key molecules on each side of the cell membrane. Cells need to stay balanced both electrically (a set number of charged particles, called ions, on each side of the cell membrane) and chemically (a set concentration of molecules, such as glucose or ATP, which give the cell energy). One way cells accomplish this is by retaining potassium, a positively charged ion, at concentrations over 20 times higher inside the cell than outside the cell. Retaining potassium is so critical for cell survival that they expend a large portion of their valuable energy maintaining potassium equilibrium by exporting sodium and importing potassium via a sodium-potassium pump.
Recall that when cells undergo necrosis, their potassium spills out into their surrounding environment. Normal amounts of programmed cell death don’t cause this. In contrast, when doctors target cancer with anti-tumor drugs there is widespread necrosis, followed by potassium release. This sudden excess of potassium causes problems. The amount of potassium disrupts the equilibrium of immune cells within the tumor microenvironment, which then leads to dysfunction in nutrient uptake and membrane charge, which hinders a cell’s ability to function properly.
This potassium imbalance in the tumor seems to strongly impact the ability of immune cells, in particular T cells, to function. It seems that when there is too much potassium outside T cells, the concentration inside T cells falls as an attempt to rebalance the system. However, this drop in intracellular potassium means that T cells can no longer use the potassium gradient to uptake nutrients. This means that while there may be nutrients present, T cells cannot access them, and therefore go into starvation mode. Once T cells begin to starve, they cease their tumor-killing actions and may even begin to regain stem-cell-like properties. T cell “stemness” is associated with survival and persistence, which is good for the T cell, but bad for fighting cancer.
All this leaves us in a tricky situation, because it seems that anti-cancer drugs might actually be suppressing our body’s natural ability to fight back against cancer. And this is not to say anyone should avoid chemotherapy ⎯ the reason we treat tumors with chemo is because they have already advanced beyond what our bodies can handle alone. Please, please, listen to your oncologist! However, this is something that researchers will have to overcome if we want to use immunotherapy effectively. One way to do this may be to use a potassium sponge, much like the chemotherapy sponge that Morgan recently wrote about. Perhaps in a few months or years, you will find an Oncobites article describing another ingenious way that researchers have found to get around this issue. Either way, this research is another revealing piece to the puzzle of cancer immunotherapy ⎯ one that will undoubtedly help us move forward to improve patient care.
In-text image created by the author with BioRender
Vodnala, S. K., et al (2019). T cell stemness and dysfunction in tumors are triggered by a common mechanism. Science, 363(6434), eaau0135.