Short-term starvation reduces IGF-1 levels to sensitize lung tumors to PD-1 immune checkpoint blockade

Abstract

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.

Impact of supervised beego, a traditional Chinese water-only fasting, on thrombosis and haemostasis

“…25 26 Caloric restriction delays disease onset and mortality in rhesus monkeys. 27 28 More encouragingly, clinical investigations in Western countries indicate that fasting reduces obesity 3 and hypertension, 7 8 improves oxidative stress, 29 30 cardiovascular disease, [31][32][33] cancer, [34][35][36][37][38] rheumatoid arthritis, 39 metabolic syndrome, 40 41 osteoarthritis, 42 fibromyalgia, 43 chronic pain, 44 memory, 45 circadian clock 46 and multiple aspects of life quality. 11 47-50 However, the safety and the biological effects of beego, the Chinese traditional fasting practice, remain completely undocumented in scientific format.…”

Innate immune remodeling by short‐term intensive fasting

“…The positive health benefits of incomplete fasting have been well documented (de Cabo & Mattson, 2019). Incomplete fasting was reported to reduce obesity (Bloom, 1959), cardiovascular diseases (Horne et al, 2008(Horne et al, , 2013Most et al, 2018), cancer (Ajona et al, 2020;Di Biase et al, 2016;Nencioni et al, 2018;Pietrocola et al, 2016;Yamaza et al, 2010), rheumatoid arthritis (Kjeldsen-Kragh et al, 1991), metabolic syndrome (Steiniger et al, 2009), osteoarthritis (Schmidt et al, 2010), fibromyalgia (Michalsen et al, 2013), and improve memory (Witte et al, 2009). Through the use of animal fasting models, the mechanism of such health benefits has been becoming clear, such as regulation via ketogenesis (Capozzi et al, 2020;López-Soldado et al, 2020;Steinhauser et al, 2018), hormone modulation (Fontana et al, 2016;Sutton et al, 2018;Volek et al, 2002), circadian clock (Gill et al, 2015), and gut microbiota changes that protect the central nervous system in autoimmunity disorders (Cignarella et al, 2018).…”

The current knowledge concerning solid cancer and therapy

“…Other ICI low responsive cold tumors are CRC and ovarian cancer. [ 194 ] By contrast, ICI is a major breakthrough for the treatment of NSCLC [ 195 ] in which PD‐1 blockade either as a monotherapy or in adjuvant with chemotherapy has now been identified as standard care for first‐line use in the NSCLC patients. [ 196 ] The response rate for NSCLC can rise to ∼42%, which is outstanding.…”