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Fasting-Mimicking Diet Is Safe and Reshapes Metabolism and Antitumor Immunity in Patients with Cancer.

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.

SUBMITTER: Vernieri C

PROVIDER: S-EPMC9762338 | biostudies-literature | 2022 Jan

REPOSITORIES: biostudies-literature

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Fasting-Mimicking Diet Is Safe and Reshapes Metabolism and Antitumor Immunity in Patients with Cancer.

Vernieri Claudio C Fucà Giovanni G Ligorio Francesca F Huber Veronica V Vingiani Andrea A Iannelli Fabio F Raimondi Alessandra A Rinchai Darawan D Frigè Gianmaria G Belfiore Antonino A Lalli Luca L Chiodoni Claudia C Cancila Valeria V Zanardi Federica F Ajazi Arta A Cortellino Salvatore S Vallacchi Viviana V Squarcina Paola P Cova Agata A Pesce Samantha S Frati Paola P Mall Raghvendra R Corsetto Paola Antonia PA Rizzo Angela Maria AM Ferraris Cristina C Folli Secondo S Garassino Marina Chiara MC Capri Giuseppe G Bianchi Giulia G Colombo Mario Paolo MP Minucci Saverio S Foiani Marco M Longo Valter Daniel VD Apolone Giovanni G Torri Valter V Pruneri Giancarlo G Bedognetti Davide D Rivoltini Licia L de Braud Filippo F

Cancer discovery 20211117 1

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 m ...[more]

PMID: 34789537

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Project description:As a safe, feasible, and inexpensive dietary intervention, fasting-mimicking diet (FMD) exhibits excellent antitumor efficacy by regulating metabolism and boosting antitumor immunity. A better understanding of the specific mechanisms underlying the immunoregulatory functions of FMD could help improve and expand the clinical application of FMD-mediated immunotherapeutic strategies. In this study, we aimed to elucidate the role of metabolic reprogramming induced by FMD in activation of antitumor immunity against colorectal cancer. Single-cell RNA sequencing analysis of intratumoral immune cells revealed that tumor-infiltrating IgA+ B cells were significantly reduced by FMD treatment, leading to the activation of antitumor immunity and tumor regression in murine colorectal cancer models. Mechanistically, FMD delayed tumor growth by repressing B-cell class switching to IgA. Therefore, FMD-induced reduction of IgA+ B cells overcame the suppression of CD8+ T cells. The immunoregulatory and antitumor effects of FMD intervention were reversed by IgA+ B-cell transfer. Moreover, FMD boosted fatty acid oxidation (FAO) to trigger RUNX3 acetylation, thus inactivating Cα gene transcription and IgA class switching. IgA+ B-cell expansion was also impeded in patients placed on FMD, while B-cell expression of carnitine palmitoyl transferase 1A (CPT1A), the rate-limiting enzyme of FAO, was increased. Furthermore, CPT1A expression was negatively correlated with both IgA+ B cells and IgA secretion within colorectal cancer. Together, these results highlight that FMD holds great promise for treating colorectal cancer. Furthermore, the degree of IgA+ B cell infiltration and FAO-associated metabolic status are potential biomarkers for evaluating FMD efficacy.SignificanceMetabolic reprogramming of B cells induced by fasting-mimicking diet suppresses IgA class switching and production to activate antitumor immunity and inhibit tumor growth. See related commentary by Bush and Perry, p. 3493.

Project description:ObjectivePreclinical evidences suggests that while fasting can reduce the side effects and toxicity of chemotherapy, it can make cancer cells more susceptible to chemotherapy. This study aimed to examine the effects of fasting mimicking diet (FMD) during neo-adjuvant chemotherapy in breast cancer (BC) patients.MethodsForty-four newly diagnosed human epidermal growth factor receptor 2-negative (HER2-negative) patients with BC were randomized equally into two groups (22 each), to receive either a fasting mimicking diet (FMD) or their regular diet for 3 days prior to and during neoadjuvant chemotherapy. This FMD was repeated every 3 weeks for 8 cycles. Efficacy, toxicity, hematologic, metabolic, and inflammatory parameters were measured and compared.ResultsThe occurrence of grade III vomiting and neutropenia in the control group was significantly higher than the FMD group (P = <0.001 and p = 0.04 respectively). Erythrocytes (p = 0.01) and neutrophils (p = 0.002) counts were significantly higher in FMD group compared to control group after cycle 8. There was a significant increase in median glucose and median insulin levels (p = 0.01 and p = 0.005, respectively) in the control group between baseline and after cycle 8. While, the median Insulin-like growth factor-1 (IGF1) (p = 0.006) and hs-CRP (p = 0.02) levels were significantly decreased in the FMD group. At the end of study (after cycle 8), the median glucose level was significantly higher in control group (p = 0.008), while the median hs-CRP level was significantly lower in FMD group (p = 0.01). The Miller and Payne pathological response 4/5 (90-100% tumor cell loss) and the radiologically complete or partial response, as measured by MRI or ultrasound before surgery occurred more frequently in FMD group compared to the controls (p = 0.01).ConclusionFasting mimicking diet was well tolerated during chemotherapy and reduced toxicity of chemotherapy and also, had beneficial effects of some metabolic parameters.Clinical trial registrationhttps://irct.behdasht.gov.ir/user/trial/61386/view.

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Fasting-Mimicking Diet Is Safe and Reshapes Metabolism and Antitumor Immunity in Patients with Cancer.

Publications

Fasting-Mimicking Diet Is Safe and Reshapes Metabolism and Antitumor Immunity in Patients with Cancer.

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