Fasting-like conditions can improve the efficacy of chemotherapy by eliciting an antitumour immune response. Therefore, it might be reasoned that the combination of fasting and immunotherapy would serve to increase tumour immunogenicity and counteract primary resistance to immune checkpoint blockade (ICB). Ajona et al. explored this possibility.
To test the effect of the combination treatment, syngeneic mouse models of lung cancer were used wherein two different tumour cell lines — 393P and LLC — were subcutaneously implanted into mice. Once tumours were established, fasting in the form of short-term starvation (STS) was carried out by withdrawing access to food during set intermittent cycles, along with administration of a PD1 antibody. STS synergized with PD1 blockade to attenuate tumour growth and increase the survival of the mice. CD8+ T cells are likely to mediate the sensitization of lung tumour cells to the action of PD1 blockade under conditions of STS as depletion of this effector cell type abolished the antitumour effect of the combination.
In the case of the 393P tumour model, mice that exhibited complete responses were protected from tumour re-challenge, consistent with induction of immunological memory. Furthermore, substitution of the PD1 antibody for a PDL1 antibody in the combination treatment was also able to inhibit LLC tumour growth.
Metabolic changes associated with fasting include lower systemic levels of insulin-like growth factor 1 (IGF1). In agreement with this, STS either with or without anti-PD1 reduced plasma IGF1 levels in tumour-bearing mice. Interestingly, lower levels of circulating IGF1 or low tumour expression of the IGF1 receptor (IGF1R) correlated with durable clinical benefit in patients with non-small-cell lung cancer treated with either anti-PD1 or anti-PDL1 therapy.
“this study supports the clinical testing of IGF1R inhibitors in combination with ICB”
In turn, this led the authors to assess the effect of anti-PD1 in conjunction with an IGF1R antagonist. The reduced tumour growth observed with this co-treatment correlated with increased numbers of tumour-infiltrating CD8+ and CD4+ T cells with less expression of exhaustion markers and decreased numbers of intratumoural Treg cells.
Overall, this study supports the clinical testing of IGF1R inhibitors in combination with ICB.
Ajona, D. et al. Short-term starvation reduces IGF-1 levels to sensitize lung tumors to PD-1 immune checkpoint blockade. Nat. Cancer 1, 75–85 (2020)
Nencioni, A. et al. Fasting and cancer: molecular mechanisms and clinical application. Nat. Rev. Cancer 18, 707–719 (2018)