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    Home > Active Ingredient News > Immunology News > Cell Sub-Journal: Simulated fasting can reshape the body's immunity and improve the effect of cancer immunotherapy

    Cell Sub-Journal: Simulated fasting can reshape the body's immunity and improve the effect of cancer immunotherapy

    • Last Update: 2022-09-22
    • Source: Internet
    • Author: User
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    Source Clove Academic


    At present, immunotherapy has made very positive progress in the treatment of melanoma, lung cancer and colorectal cancer, however, the effectiveness of immunotherapy has so far been limited to specific cancer types, and there are still most patients who are not active in
    the treatment of immunotherapy.

    In addition, it is worth noting that immunotherapy, even the combination of immunotherapy, also increases the risk of adverse events, which also severely limits their use
    in the clinic.


    Over the past decade, the use of some nutrients to simulate fasting, the Fasting Mimicking Diet (FMD), has been beneficial to promote the recovery of the immune system and work synergistically with chemotherapy, radiation therapy, hormone therapy, etc.
    to achieve better anti-tumor responses, and even eradicate
    tumors in some preclinical tumor models.


    On August 23, 2022, a research team from the FIRC Institute of Molecular Oncology in Italy, among others, published a research paper titled Fasting renders immunotherapy effective against low-immunogenic breast cancer while reducing side effects at Cell Reports, demonstrating that fasting simulated diet (FMD) It can enhance the anti-tumor immune response of low immunogenic triple-negative breast cancer (TNBC) and reduce its side effects
    .


    Fasting simulated diets can act on the tumor microenvironment, increasing the effects
    of immunotherapy (anti-PD-L1 and anti-OX40) in low-immunogenic triple-negative breast cancer (TNBC).

    In addition, FMD can also reduce the occurrence
    of immune-related adverse events (irAEs) by preventing excessive activation of the immune response.



    Fasting mock diet combined with anti-OX40/anti-PD-L1 can stop the progression
    of breast cancer First, the researchers implanted 4T1 breast cancer cells in situ into the breast fat pads of mice, then treated with anti-OX40/anti-PD-L1 alone or in combination, and set up fasting simulated diet (FMD) treatment groups and standard diet groups (AL).


    The results showed that the FMD group treated with IgG alone showed inhibition of tumor growth compared to the standard diet group; Anti-PD-L1 monotherapy showed no antitumor effect in either the AL group and the FMD group; Anti-OX40 treatment had no antitumor effect in mice in the AL group, while in mice fed FMD it delayed tumor growth
    .

    Combination anti-OX40/anti-PD-L1 therapy reduces tumor mass in the standard diet group and is more effective
    in combination with FMD.

    At the same time, FMD combined with immunotherapy significantly prolonged mouse survival compared with other groups
    .
    To determine the role of the immune system in it, they used the same treatment regimen
    in NSG immunodeficiency breast cancer mice.

    Fasting simulated diet plus anti-OX40/anti-PD-L1 therapy is no longer effective in immunodeficient mice, suggesting that the antitumor effect of FMD in combination with anti-OX40/anti-PD-L1 therapy is immune system-mediated
    .

    Fasting mock diet combined with anti-OX40/anti-PD-L1 treatment enhances anti-tumor response
    by promoting T cell activation To explore how fasting mock diets can improve anti-tumor activity, they isolated CD45-positive tumor invasive immune cells from a mouse model of breast cancer and performed single-cell transcriptome sequencing (scRNA-seq).


    Based on an unbiased clustering method, they identified a total of 14 cell subsets
    .

    Among them, compared with all other experimental conditions, the FMD combined immunotherapy group activated CD8 T cells and CD4 T cells were relatively rich
    .

    Compared with other experimental groups, fasting simulated diet combined with immunotherapy also increased the expression of cytotoxic activity-related genes and CD8 T cell activation percentage
    in tumor immune infiltration.

    In contrast, genes involved in negative regulation of cytotoxicity were significantly downregulated
    in the FMD combined immunotherapy group.

    Subsequently, they also confirmed the results
    of the above transcriptome analysis at protein levels by flow cytometry and immunohistochemistry.

    Subsequent experimental results also show that not only for adaptive immunity, FMD can also remodel the body's innate immune system, further promoting anti-tumor immunity
    .
    Fasting simulated diet remodels tumor interstitium, normalizing
    tumor blood vessels Since the massive deposition of collagen in breast cancer promotes tumor development and progression, often associated with poor prognosis, they investigated whether FMD affects collagen remodeling and tumor matrix structure
    .

    They observed that the FMD group had less collagen fiber deposition in the tumor bed and a lower
    linear and denser collagen fibers compared to the standard diet group.
    The normalization of tumor blood vessels can improve the efficacy of immunotherapy, improve tumor vascular perfusion, and promote the infiltration of immune effector cells in the tumor microenvironment
    .

    To determine whether FMD in combination with immunotherapy also affected tumor vascularity, they analyzed tumor vascular conditions
    during treatment.

    The number of tumor endothelial cells and pericyte cells in the FMD group decreased compared to the standard diet group, but the pericyclic cell localization was not impaired
    .

    In the standard diet group, endothelial cells are more elongated, forming a dense network of blood vessels; Conversely, in the FMD group, endothelial cells appear immature and branch poorly
    .

    This suggests that FMD promotes infiltration
    of immune cells by reducing collagen accumulation and reshaping tumor vascular networks.
    Fasting simulated diets can reduce the risk
    of allergic reactions associated with immunotherapy Because some patients are prone to serious adverse reactions, the use
    of immunotherapy is limited.

    The researchers found that repeated single or combination treatments against PD-L1 and anti-OX-40 had fatal side effects in mice fed standard feeds, but this fatal effect
    was not observed in mice that also received a fasting simulated diet.

    Further analysis showed that FMD-induced changes in lymphocytes, monocytes, granulocytes, and platelets can prevent or attenuate the release of factors that determine allergic reactions, such as MPO, histamine, and VEGF, without affecting immunotherapy efficacy
    .

    Fasting simulation diets are also effective
    in the TS/A breast cancer model, and they explored whether FMD and anti-OX40/anti-PD-L1 therapy can also be effective in treating another model of low immunogenic breast tumors, TS/A
    .

    They observed that FMD improved the anti-tumor response in anti-OX40/anti-PD-L1 therapy for TS/A breast cancer and effectively stopped tumor growth compared to the standard diet, while FMD alone did not have a significant anti-tumor effect in TS/A tumors
    .
    In the TS/A model, FMD itself does not increase immune infiltration of CD3 T cells and CD8 T cells, does not affect the activation of CD8 T cells, but can enhance cytotoxicity and promote CD8 T lymphocyte proliferation
    .

    In addition, a fasting mimetic diet alone, along with a standard diet combined with immunotherapy, increased the percentage of immunosuppressive Treg cells, while FMD in combination with immunotherapy prevented this increase
    .

    At the same time, as observed in the 4T1 model, FMD not only remodeled the tumor microenvironment cellular components of the TS/A model, but also reshaped the structure and tissue
    of collagen fibers in the tumor bed.
    In summary, the results of this study suggest that fasting simulated diet combined with anti-OX40/anti-PD-L1 therapy enhances the anti-tumor immune response of two different low immunogenic triple-negative breast cancer subtypes (4T1 and TS/A) and reduces tumor volume
    .

    More in-depth analysis suggests that fasting simulated diets may enhance the efficacy of immunotherapy by remodeling the immune system and tumor microenvironment
    .
    Therefore, fasting simulated diets may represent a promising nutritional intervention that should be tested in future clinical trials to sensitize hypo-immunogenic tumors to improve the application of immunotherapy for the benefit of more patients
    .
    FMD is a dietary approach
    proposed by Valter Longo, the study's corresponding author.

    The method is composed of low-calorie, low-sugar, low-protein, but high-unsaturated fatty acid foods, and contains a large amount of water and plant fiber, trying to reduce the total calorie intake
    .

    FMD is generally performed at a monthly frequency for 5 days, which gives the body enough time to undergo fasting-related adaptive changes that are thought to help fight aging and improve health
    .
    In 2014, Professor Valter Longo founded L-Nutra and subsequently released the first commercial FMD product, ProLon, to make FMD a standardized clinically usable product
    .
    Special reminder: The conclusions of this study are limited to tumor mouse models and are for academic research reference
    only.

    Not confirmed in clinical studies, relevant patients should not be arbitrarily imitated.

    Thesis link: https://doi.
    org/10.
    1016/j.
    celrep.
    2022.
    111256
    open reprint welcome to forward to the circle of friends and WeChat group

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