How Lactic acid inhibits anti-tumor defenses

Lactic acid, or lactate, is created in enormous numbers by cancer cells, and this lactic acid undermines our defence against tumours has long been known in cancer research. However, until recently, we have no idea how this happened. Prof Jo Van Ginderachter, an immunologist and cancer researcher at the Vrije Universiteit Brussel and the Flemish Institute for Biotechnology (VIB), and PhD student Xenia Geeraerts (VUB), Prof Sarah-Maria Fendt (VIB-KU Leuven), and Prof Jan Van den Bossche of the University of Amsterdam, discovered the answer in collaboration with Prof Sarah-Maria Fendt (VIB-KU Leuven) and Prof Jan The findings were published in Cell Reports, a prestigious magazine.

Van Ginderachter: I'm Van Ginderachter, and I'm "We discovered that macrophages, a type of immune cell, use lactic acid as an energy source. Macrophages are seen in huge numbers in tumours, but they are fooled by the tumour to aid in its growth. The cancer cells' lactic acid keeps the macrophages alive, but they eventually grow into tumor-promoting cells. The lactic acid causes macrophages to paralyse other 'killer' immune cells that can recognise and destroy cancer cells, weakening tumour immunity."

Immunotherapy resistance

As a result, macrophages may play a role in tumour resistance to immunotherapy.

"This high level of lactic acid in tumours may have immunotherapy implications," Van Ginderachter says. "In immunotherapy, our bodies' own 'killer' immune cells are activated to attack cancer cells in the most effective way possible. Despite the fact that this therapy is very promising and works well for skin cancer and is increasingly being used for lung cancer, for example, only a small percentage of patients respond well to it. One of the reasons is that macrophages feed on the lactic acid in the tumour, which turns off the 'killing immune cells' that immunotherapy is supposed to promote. So we need to be able to inhibit immune-disrupting cells like macrophages while yet increasing immunotherapy success."

Lactic acid production can be reduced or neutralised.

As a result, it's critical to investigate how lactic acid generation in tumours might be reduced. Lactic acid is found in considerable amounts in a variety of tumour forms, according to Van Ginderachter.

"Lactac acid is produced in large quantities by cancer cells. There are other places in tumours with very low oxygen concentrations, where lactic acid levels can rise to much higher levels. You can try to stop lactic acid from being produced in tumours. This is an approach that is now being tested in preliminary clinical trials. However, because we know that many other cells in the tumour create lactic acid in addition to cancer cells, it needs to be seen if these treatments will be adequate to reduce lactate to the point where its effect on tumor-supporting macrophages is neutralised. On the other hand, lactic acid can be neutralised by supplying a buffer solution, for example. This is also the subject of preliminary investigation. Another possibility is to employ drugs to prevent macrophages from consuming lactic acid. It's critical that such a drug is non-toxic and that it reaches the tumour in a precise manner. In our research, we're also looking at these issues so that future drugs can be given directly to the tumour or macrophages, avoiding adverse effects."

Reference:

Xenia Geeraerts, Juan Fernández-Garcia, Felix J. Hartmann, Kyra E. de Goede, Liesbet Martens, Yvon Elkrim, Ayla Debraekeleer, Benoit Stijlemans, Anke Vandekeere, Gianmarco Rinaldi, Riet De Rycke, Mélanie Planque, Dorien Broekaert, Elisa Meinster, Emile Clappaert, Pauline Bardet, Aleksandar Murgaski, Conny Gysemans, Frank Aboubakar Nana, Yvan Saeys, Sean C. Bendall, Damya Laoui, Jan Van den Bossche, Sarah-Maria Fendt, Jo A. Van Ginderachter. Macrophages are metabolically heterogeneous within the tumor microenvironment. Cell Reports, 2021; 37 (13): 110171 DOI: 10.1016/j.celrep.2021.110171