Short Term Starvation Enhances Lung Cancer Treatment by Reducing IGF-1 Levels

The outcome of cancer treatment depends heavily on the ability of the patient’s immune cells to effectively combat the tumour. Tumours may protect themselves from the immune system by activating programmed cell death protein 1 (PD-1), a receptor on T cells that acts as an ‘immune checkpoint’, and usually serves to help prevent autoimmunity. When a T cell recognises a cell expressing the PD1 ligand, activation of that T cell is suppressed. Cancer cells make use of this pathway by expressing PD1 ligand, signalling that they belong in the body and should not be destroyed.

Antibodies can be used to block the PD-1 receptor, meaning cancer cells cannot prevent T cell activation:

Blocking the PD-1 pathway has proven to be effective as a treatment in some cases, however many patients do not respond to this intervention. The study published here in Nature Cancer suggests that there may be a way to improve the effectiveness of PD-1 inhibition. When tumour-carrying mice were subjected to intermittent food withdrawal, PD-1 inhibition was more effective at reducing tumour growth than either treatment alone. The researchers linked this effect to the levels of insulin-like growth factor (IGF-1), and found that inhibiting IGF-1 was also effective in reducing tumour growth.

This research was carried out in mice carrying lung cancer cells. The question now is whether the effects of combined IGF-1 and PD-1 inhibition will translate to other cancers in humans. There have been studies suggesting that fasting is beneficial in some cancer patients, but fasting can also negatively impact cancer treatment, such as in those who are underweight. Research in this area is still ongoing, and larger clinical trials are needed to fully ascertain the risks and benefits.

Harnessing the immune system by blocking the programmed cell death protein 1 (PD-1) pathway has been a major breakthrough in non-small-cell lung cancer treatment. Nonetheless, many patients fail to respond to PD-1 inhibition. Using three syngeneic models, we demonstrate that short-term starvation synergizes with PD-1 blockade to inhibit lung cancer progression and metastasis. This antitumor activity was linked to a reduction in circulating insulin-like growth factor 1 (IGF-1) and a downregulation of IGF-1 receptor (IGF-1R) signaling in tumor cells. A combined inhibition of IGF-1R and PD-1 synergistically reduced tumor growth in mice. This effect required CD8 cells, boosted the intratumoral CD8/T_reg ratio and led to the development of tumor-specific immunity. In patients with non-small-cell lung cancer, high plasma levels of IGF-1 or high IGF-1R expression in tumors was associated with resistance to anti-PD-1–programmed death-ligand 1 immunotherapy. In conclusion, our data strongly support the clinical evaluation of IGF-1 modulators in combination with PD-1 blockade.

Ajona, D., Ortiz-Espinosa, S., Lozano, T., Exposito, F., Calvo, A., & Valencia, K. et al. (2020). Short-term starvation reduces IGF-1 levels to sensitize lung tumors to PD-1 immune checkpoint blockade. Nature Cancer, 1(1), 75-85. doi: 10.1038/s43018-019-0007-9