Fasting-Mimicking Diet Is Safe and Reshapes Metabolism and Antitumor Immunity in Patients with Cancer
Claudio Vernieri, Giovanni Fucà, Francesca Ligorio, Veronica Huber, Andrea Vingiani, Fabio Iannelli, Alessandra Raimondi, Darawan Rinchai, Gianmaria Frigè, Antonino Belfiore, Luca Lalli, Claudia Chiodoni, Valeria Cancila, Federica Zanardi, Arta Ajazi, Salvatore Cortellino, Viviana Vallacchi, Paola Squarcina, Agata Cova, Samantha Pesce, Paola Frati, Raghvendra Mall, Paola Antonia Corsetto, Angela Maria Rizzo, Cristina Ferraris, Secondo Folli, Marina Chiara Garassino, Giuseppe Capri, Giulia Bianchi, Mario Paolo Colombo, Saverio Minucci, Marco Foiani, Valter Daniel Longo, Giovanni Apolone, Valter Torri, Giancarlo Pruneri, Davide Bedognetti, Licia Rivoltini, Filippo de Braud, Claudio Vernieri, Giovanni Fucà, Francesca Ligorio, Veronica Huber, Andrea Vingiani, Fabio Iannelli, Alessandra Raimondi, Darawan Rinchai, Gianmaria Frigè, Antonino Belfiore, Luca Lalli, Claudia Chiodoni, Valeria Cancila, Federica Zanardi, Arta Ajazi, Salvatore Cortellino, Viviana Vallacchi, Paola Squarcina, Agata Cova, Samantha Pesce, Paola Frati, Raghvendra Mall, Paola Antonia Corsetto, Angela Maria Rizzo, Cristina Ferraris, Secondo Folli, Marina Chiara Garassino, Giuseppe Capri, Giulia Bianchi, Mario Paolo Colombo, Saverio Minucci, Marco Foiani, Valter Daniel Longo, Giovanni Apolone, Valter Torri, Giancarlo Pruneri, Davide Bedognetti, Licia Rivoltini, Filippo de Braud
Abstract
In tumor-bearing mice, cyclic fasting or fasting-mimicking diets (FMD) enhance the activity of antineoplastic treatments by modulating systemic metabolism and boosting antitumor immunity. Here we conducted a clinical trial to investigate the safety and biological effects of cyclic, five-day FMD in combination with standard antitumor therapies. In 101 patients, the FMD was safe, feasible, and resulted in a consistent decrease of blood glucose and growth factor concentration, thus recapitulating metabolic changes that mediate fasting/FMD anticancer effects in preclinical experiments. Integrated transcriptomic and deep-phenotyping analyses revealed that FMD profoundly reshapes anticancer immunity by inducing the contraction of peripheral blood immunosuppressive myeloid and regulatory T-cell compartments, paralleled by enhanced intratumor Th1/cytotoxic responses and an enrichment of IFNγ and other immune signatures associated with better clinical outcomes in patients with cancer. Our findings lay the foundations for phase II/III clinical trials aimed at investigating FMD antitumor efficacy in combination with standard antineoplastic treatments. SIGNIFICANCE: Cyclic FMD is well tolerated and causes remarkable systemic metabolic changes in patients with different tumor types and treated with concomitant antitumor therapies. In addition, the FMD reshapes systemic and intratumor immunity, finally activating several antitumor immune programs. Phase II/III clinical trials are needed to investigate FMD antitumor activity/efficacy.This article is highlighted in the In This Issue feature, p. 1.
©2021 The Authors; Published by the American Association for Cancer Research.
Figures
References
- Lee C, Raffaghello L, Brandhorst S, Safdie FM, Bianchi G, Martin-Montalvo A, et al. . Fasting cycles retard growth of tumors and sensitize a range of cancer cell types to chemotherapy. Sci Transl Med 2012;4:124ra27.
- Lee C, Safdie FM, Raffaghello L, Wei M, Madia F, Parrella E, et al. . Reduced levels of IGF-I mediate differential protection of normal and cancer cells in response to fasting and improve chemotherapeutic index. Cancer Res 2010;70:1564–72.
- Di Biase S, Lee C, Brandhorst S, Manes B, Buono R, Cheng CW, et al. . Fasting-mimicking diet reduces HO-1 to promote T cell-mediated tumor cytotoxicity. Cancer Cell 2016;30:136–46.
- Di Tano M, Raucci F, Vernieri C, Caffa I, Buono R, Fanti M, et al. . Synergistic effect of fasting-mimicking diet and vitamin C against KRAS mutated cancers. Nat Commun 2020;11:2332.
- Ajona D, S. O-E, Lozano T, Exposito F, Calvo A, Valencia K, et al. . Short-term starvation reduces IGF-1 levels to sensitize lung tumors to PD-1 immune checkpoint blockade. Nat Cancer 2020;1:75–85.
- Caffa I, Spagnolo V, Vernieri C, Valdemarin F, Becherini P, Wei M, et al. . Fasting-mimicking diet and hormone therapy induce breast cancer regression. Nature 2020;583:620–4.
- de Groot S, Lugtenberg RT, Cohen D, Welters MJP, Ehsan I, Vreeswijk MPG, et al. . Fasting mimicking diet as an adjunct to neoadjuvant chemotherapy for breast cancer in the multicentre randomized phase 2 DIRECT trial. Nat Commun 2020;11:3083.
- Bronte V, Brandau S, Chen SH, Colombo MP, Frey AB, Greten TF, et al. . Recommendations for myeloid-derived suppressor cell nomenclature and characterization standards. Nat Commun 2016;7:12150.
- Filipazzi P, Valenti R, Huber V, Pilla L, Canese P, Iero M, et al. . Identification of a new subset of myeloid suppressor cells in peripheral blood of melanoma patients with modulation by a granulocyte-macrophage colony-stimulation factor-based antitumor vaccine. J Clin Oncol 2007;25:2546–53.
- Roux C, Jafari SM, Shinde R, Duncan G, Cescon DW, Silvester J, et al. . Reactive oxygen species modulate macrophage immunosuppressive phenotype through the up-regulation of PD-L1. Proc Natl Acad Sci U S A 2019;116:4326–35.
- Moretta L. Dissecting CD56dim human NK cells. Blood 2010;116:3689–91.
- Anderson AC, Joller N, Kuchroo VK. Lag-3, Tim-3, and TIGIT: co-inhibitory receptors with specialized functions in immune regulation. Immunity 2016;44:989–1004.
- DeNardo DG, Brennan DJ, Rexhepaj E, Ruffell B, Shiao SL, Madden SF, et al. . Leukocyte complexity predicts breast cancer survival and functionally regulates response to chemotherapy. Cancer Discov 2011;1:54–67.
- Charoentong P, Finotello F, Angelova M, Mayer C, Efremova M, Rieder D, et al. . Pan-cancer immunogenomic analyses reveal genotype-immunophenotype relationships and predictors of response to checkpoint blockade. Cell Rep 2017;18:248–62.
- Aran D, Hu Z, Butte AJ. xCell: digitally portraying the tissue cellular heterogeneity landscape. Genome Biol 2017;18:220.
- Benci JL, Johnson LR, Choa R, Xu Y, Qiu J, Zhou Z, et al. . Opposing functions of interferon coordinate adaptive and innate immune responses to cancer immune checkpoint blockade. Cell 2019;178:933–48.
- Condamine T, Dominguez GA, Youn JI, Kossenkov AV, Mony S, Alicea-Torres K, et al. . Lectin-type oxidized LDL receptor-1 distinguishes population of human polymorphonuclear myeloid-derived suppressor cells in cancer patients. Sci Immunol 2016;1:aaf8943.
- Krieg C, Nowicka M, Guglietta S, Schindler S, Hartmann FJ, Weber LM, et al. . High-dimensional single-cell analysis predicts response to anti-PD-1 immunotherapy. Nat Med 2018;24:144–53.
- Wang L, Simons DL, Lu X, Tu TY, Avalos C, Chang AY, et al. . Breast cancer induces systemic immune changes on cytokine signaling in peripheral blood monocytes and lymphocytes. EBioMedicine 2020;52:102631.
- Fromm PD, Silveira PA, Hsu JL, Papadimitrious MS, Lo TH, Ju X, et al. . Distinguishing human peripheral blood CD16(+) myeloid cells based on phenotypic characteristics. J Leukoc Biol 2020;107:323–39.
- Gerlach C, Moseman EA, Loughhead SM, Alvarez D, Zwijnenburg AJ, Waanders L, et al. . The chemokine receptor CX3CR1 defines three antigen-experienced CD8 T cell subsets with distinct roles in immune surveillance and homeostasis. Immunity 2016;45:1270–84.
- Yan Y, Cao S, Liu X, Harrington SM, Bindeman WE, Adjei AA, et al. . CX3CR1 identifies PD-1 therapy-responsive CD8+ T cells that withstand chemotherapy during cancer chemoimmunotherapy. JCI Insight 2018;3:e97828.
- Flippe L, Bezie S, Anegon I, Guillonneau C. Future prospects for CD8(+) regulatory T cells in immune tolerance. Immunol Rev 2019;292:209–24.
- André F, Ciruelos E, Rubovszky G, Campone M, Loibl S, Rugo HS, et al. . Alpelisib for PIK3CA-mutated, hormone receptor–positive advanced breast cancer. N Engl J Med 2019;380:1929–40.
- Gandhi L, Rodríguez-Abreu D, Gadgeel S, Esteban E, Felip E, De Angelis F, et al. . Pembrolizumab plus chemotherapy in metastatic non–small-cell lung cancer. N Engl J Med 2018;378:2078–92.
- Cremolini C, Antoniotti C, Rossini D, Lonardi S, Loupakis F, Pietrantonio F, et al. . Upfront FOLFOXIRI plus bevacizumab and reintroduction after progression versus mFOLFOX6 plus bevacizumab followed by FOLFIRI plus bevacizumab in the treatment of patients with metastatic colorectal cancer (TRIBE2): a multicentre, open-label, phase 3, randomised, controlled trial. Lancet Oncol 2020;21:497–507.
- Vernieri C, Ligorio F, Zattarin E, Rivoltini L, de Braud F. Fasting-mimicking diet plus chemotherapy in breast cancer treatment. Nat Commun 2020;11:4274.
- Argiles JM, Busquets S, Stemmler B, Lopez-Soriano FJ. Cancer cachexia: understanding the molecular basis. Nat Rev Cancer 2014;14:754–62.
- Elgendy M, Ciro M, Hosseini A, Weiszmann J, Mazzarella L, Ferrari E, et al. . Combination of hypoglycemia and metformin impairs tumor metabolic plasticity and growth by modulating the PP2A-GSK3beta-MCL-1 axis. Cancer Cell 2019;35:798–815.
- Vernieri C, Casola S, Foiani M, Pietrantonio F, de Braud F, Longo V. Targeting cancer metabolism: dietary and pharmacologic interventions. Cancer Discov 2016;6:1315–33.
- Dorff TB, Groshen S, Garcia A, Shah M, Tsao-Wei D, Pham H, et al. . Safety and feasibility of fasting in combination with platinum-based chemotherapy. BMC Cancer 2016;16:360.
- Bauersfeld SP, Kessler CS, Wischnewsky M, Jaensch A, Steckhan N, Stange R, et al. . The effects of short-term fasting on quality of life and tolerance to chemotherapy in patients with breast and ovarian cancer: a randomized cross-over pilot study. BMC Cancer 2018;18:476.
- de Groot S, Vreeswijk MP, Welters MJ, Gravesteijn G, Boei JJ, Jochems A, et al. . The effects of short-term fasting on tolerance to (neo) adjuvant chemotherapy in HER2-negative breast cancer patients: a randomized pilot study. BMC Cancer 2015;15:652.
- Ferrere G, Tidjani Alou M, Liu P, Goubet AG, Fidelle M, Kepp O, et al. . Ketogenic diet and ketone bodies enhance the anticancer effects of PD-1 blockade. JCI Insight 2021;6:e145207.
- Jordan S, Tung N, Casanova-Acebes M, Chang C, Cantoni C, Zhang D, et al. . Dietary intake regulates the circulating inflammatory monocyte pool. Cell 2019;178:1102–14.
- Li W, Tanikawa T, Kryczek I, Xia H, Li G, Wu K, et al. . Aerobic glycolysis controls myeloid-derived suppressor cells and tumor immunity via a specific CEBPB isoform in triple-negative breast cancer. Cell Metab 2018;28:87–103.
- De Rosa V, Galgani M, Porcellini A, Colamatteo A, Santopaolo M, Zuchegna C, et al. . Glycolysis controls the induction of human regulatory T cells by modulating the expression of FOXP3 exon 2 splicing variants. Nat Immunol 2015;16:1174–84.
- Bilbao D, Luciani L, Johannesson B, Piszczek A, Rosenthal N. Insulin-like growth factor-1 stimulates regulatory T cells and suppresses autoimmune disease. EMBO Mol Med 2014;6:1423–35.
- Newton R, Priyadharshini B, Turka LA. Immunometabolism of regulatory T cells. Nat Immunol 2016;17:618–25.
- Brand A, Singer K, Koehl GE, Kolitzus M, Schoenhammer G, Thiel A, et al. . LDHA-associated lactic acid production blunts tumor immunosurveillance by T and NK cells. Cell Metab 2016;24:657–71.
- Ho PC, Bihuniak JD, Macintyre AN, Staron M, Liu X, Amezquita R, et al. . Phosphoenolpyruvate is a metabolic checkpoint of anti-tumor T cell responses. Cell 2015;162:1217–28.
- Cascone T, McKenzie JA, Mbofung RM, Punt S, Wang Z, Xu C, et al. . Increased tumor glycolysis characterizes immune resistance to adoptive T cell therapy. Cell Metab 2018;27:977–87.
- Collins N, Han SJ, Enamorado M, Link VM, Huang B, Moseman EA, et al. . The bone marrow protects and optimizes immunological memory during dietary restriction. Cell 2019;178:1088–101.
- Mlecnik B, Tosolini M, Charoentong P, Kirilovsky A, Bindea G, Berger A, et al. . Biomolecular network reconstruction identifies T-cell homing factors associated with survival in colorectal cancer. Gastroenterology 2010;138:1429–40.
- Bedognetti D, Spivey TL, Zhao Y, Uccellini L, Tomei S, Dudley ME, et al. . CXCR3/CCR5 pathways in metastatic melanoma patients treated with adoptive therapy and interleukin-2. Br J Cancer 2013;109:2412–23.
- Litchfield K, Reading JL, Puttick C, Thakkar K, Abbosh C, Bentham R, et al. . Meta-analysis of tumor- and T cell-intrinsic mechanisms of sensitization to checkpoint inhibition. Cell 2021;184:596–614.
- Galon J, Angell HK, Bedognetti D, Marincola FM. The continuum of cancer immunosurveillance: prognostic, predictive, and mechanistic signatures. Immunity 2013;39:11–26.
- Orillion A, Damayanti NP, Shen L, Adelaiye-Ogala R, Affronti H, Elbanna M, et al. . Dietary protein restriction reprograms tumor-associated macrophages and enhances immunotherapy. Clin Cancer Res 2018;24:6383–95.
- Rubio-Patino C, Bossowski JP, De Donatis GM, Mondragon L, Villa E, Aira LE, et al. . Low-protein diet induces IRE1alpha-dependent anticancer immunosurveillance. Cell Metab 2018;27:828–42.
- Green SJ, Dahlberg S. Planned versus attained design in phase II clinical trials. Stat Med 1992;11:853–62.
Source: PubMed