Putting tumours on a diet

The efficacy of chemotherapy in many cases relies on stimulation of an anticancer immune response, and can also be improved through fasting. Two papers now bring these elements together and show that specific diets or pharmacological agents that mimic fasting inhibit tumour growth in combination with chemotherapy through effects on the immune system.

Di Biase, Lee et al. investigated whether a fasting-mimicking diet (FMD, consisting of low calories, protein and sugar) would improve chemotherapy, as previously shown for short-term starvation (water intake only), because a FMD would likely be better tolerated by patients. Indeed, FMD improved tumour responses to chemotherapy as much as short-term starvation in two immunocompetent mouse models (4T1 breast cancer and B16 melanoma). The FMD plus doxorubicin chemotherapy increased the numbers of tumour-infiltrating CD8⁺ cytotoxic T cells in both mouse models; confirming the importance of the CD8⁺ cells, the FMD did not improve doxorubicin efficacy against 4T1 tumours in mice lacking all T cells or CD8⁺ cells specifically. CD8⁺ T cell depletion also correlated with increased numbers of regulatory T cells (T_reg cells). These T cell changes might explain the improved efficacy of chemotherapy.

Gene expression analysis of 4T1 cells grown in culture conditions mimicking the FMD indicated reduced expression of Hmox1, which encodes haem oxygenase 1 (HO1, which has roles in protecting cells from oxidative damage); this was confirmed in grafted 4T1 tumours. In FMD-like culture conditions, activation or overexpression of HO1 reversed the sensitization of 4T1 cells to chemotherapy, whereas inhibition of HO1 in normal culture conditions sensitized the cells to chemotherapy. Similar results were observed in vivo; tumours subjected to a FMD that had high HO1 also had lower levels of CD8⁺ T cells and increased levels of T_reg cells.

Credit: Lara Crow/NPG

Pietrocola, Pol et al. hypothesized that autophagy, which is induced by starvation, might have a role in the effects of fasting on chemotherapy efficacy. They observed that this beneficial effect of fasting in a mouse model of fibrosarcoma was lost in mice that had no T cells (similar to Di Biase, Lee et al.), and it was also lost in autophagy-deficient tumours. Furthermore, treatment of cultured cancer cells with caloric restriction mimetics (CRMs), compounds that mimic the biochemical effects of starvation through reduction of protein acetylation, stimulated autophagy. The CRM hydroxycitrate also improved chemotherapy efficacy in immunocompetent mouse models of fibrosarcoma, colorectal cancer, non-small cell lung cancer and breast cancer. Similar results were observed both with other CRMs and with compounds that induce autophagy.

The improved efficacy of chemotherapy in combination with these compounds was lost in mice lacking T cells; CD8⁺ T cells in particular were required for the effect observed with hydroxycitrate (the effects of the other compounds were not tested in CD8⁺ T cell-depleted mice). This combination therapy also reduced T_reg cell infiltration of tumours; T_reg cell depletion alone led to regression of fibrosarcomas and lung tumours in mice, and hydroxycitrate treatment did not further augment this effect, suggesting that the reduction in T_reg cells is the main mechanism by which hydroxycitrate improves the efficacy of chemotherapy. Furthermore, the induction of autophagy was crucial as only autophagy-competent tumours responded to the hydroxycitrate and chemotherapy combination or exhibited depletion of T_reg cells. Interestingly, hydroxycitrate alone limited the growth of lung tumours in Kras^G12D mice, in a mechanism that also required autophagy and reduced T_reg cell infiltration, suggesting that CRMs might also have cancer-preventive effects.

explain the mechanisms by which fasting might improve therapeutic outcomes

Overall, these papers not only suggest ways in which we might improve on the efficacy of chemotherapy and increase antitumour immune responses, but also begin to explain the mechanisms by which fasting might improve therapeutic outcomes.