POTENTIAL RISKS AND BENEFITS OF INTERMITTENT FASTING IN CANCER PREVENTION AND TREATMENT.
The relationship between T cells and intermittent fasting involves several key aspects:
1. Autophagy: Intermittent fasting triggers a process called autophagy, where cells break down and remove damaged components. This can be particularly beneficial for T cells because it helps remove dysfunctional or worn-out cellular machinery, keeping T cells more effective and healthy(1).
2. Metabolic Flexibility(ketosis) : During fasting periods, the body switches to using stored fats for energy instead of glucose. T cells are known to be highly adaptable to using these fatty acids and ketones as fuel sources. This metabolic flexibility allows T cells to maintain their function and continue patrolling the body for pathogens even when glucose is scarce(2).
3. Stem Cell Renewal: Intermittent fasting has been shown to stimulate the regeneration of hematopoietic stem cells in the bone marrow. These stem cells are responsible for producing new immune cells, including T cells. Enhanced stem cell activity can lead to the production of more and potentially more potent T cells(3).
4. Reduction in Inflammation: Chronic inflammation can negatively impact T cell function. Intermittent fasting has been associated with a reduction in systemic inflammation, creating a more favorable environment for T cells to operate effectively(4).
5. Hormonal Changes: Fasting can influence the secretion of hormones like insulin and IGF-1. These hormonal changes can impact T cell proliferation and function, potentially enhancing their ability to respond to infections(5,6).
6. Immune Memory: T cells play a crucial role in immunological memory, which allows the immune system to respond more effectively to previously encountered pathogens. Intermittent fasting may support the formation and maintenance of this memory, ensuring a more robust T cell response upon re-exposure to the same threat(7).
MOA OF T-CELL AGAINST CANCER
T cells play a crucial role in the immune system's defense against cancer cells through several mechanisms of action. Here, we'll explore the various ways T cells target and eliminate cancer cells in detail:
1. Direct Cytotoxicity (CD8+ T Cells):
Recognition: Cytotoxic T cells (CD8+) can recognize cancer cells by binding to specific antigens presented on the cancer cell's surface through major histocompatibility complex (MHC) class I molecules. Perforin and Granzymes: Upon recognition, CD8+ T cells release cytotoxic granules containing molecules like perforin and granzymes. Perforin creates pores in the cancer cell membrane, allowing granzymes to enter the cancer cell. Apoptosis: Granzymes trigger apoptosis, a form of programmed cell death, within the cancer cell, leading to its destruction(8).
2. Indirect Cytotoxicity (CD4+ T Cells): Helper Function: CD4+ T cells, also known as helper T cells, indirectly support the cytotoxic activity of CD8+ T cells by releasing cytokines like interferon-gamma (IFN-γ). IFN-γ enhances the ability of CD8+ T cells to kill cancer cells.
3. Memory T Cells:
Long-term Immunity: After an initial encounter with cancer cells, some activated T cells become memory T cells. These memory T cells remain in the body, prepared to respond rapidly if the cancer returns, providing long-term immunity.
4. Checkpoint Inhibition:
Immune Checkpoints: Cancer cells often exploit immune checkpoints, such as PD-1 (programmed cell death protein 1) and CTLA-4 (cytotoxic T-lymphocyte-associated protein 4), to evade T cell attack. Checkpoint Inhibitors: Immunotherapy drugs called checkpoint inhibitors block these checkpoints, "releasing the brakes" on T cells and allowing them to mount a stronger attack against cancer cells(9).
5. CAR-T Cell Therapy (Chimeric Antigen Receptor T Cells):
Engineering T Cells: In CAR-T cell therapy, T cells are genetically engineered to express chimeric antigen receptors (CARs) specific for a particular cancer cell antigen.
Targeting Cancer: These modified T cells can recognize and target cancer cells with precision, enhancing their ability to attack cancer cells.
6. Antigen Recognition and Adaptation:
T Cell Receptors (TCRs): T cells have T cell receptors (TCRs) that are highly specific for antigens. They can adapt and evolve to recognize new cancer cell antigens that may emerge due to mutations or changes in the tumor microenvironment.
7. Tumor-Infiltrating Lymphocytes (TILs):
Infiltrating the Tumor: Some T cells, known as tumor-infiltrating lymphocytes (TILs), migrate into the tumor microenvironment, where they directly engage with cancer cells.
8. Secretion of Cytokines:
Cytokine Release: T cells release various cytokines, including interleukins and tumor necrosis factor (TNF), which can have multiple effects on cancer cells. These cytokines can promote inflammation, recruit other immune cells, and inhibit cancer cell growth.
9. Adaptive Immunity and Antigen Presentation:
Antigen Presentation: Dendritic cells and other antigen-presenting cells capture cancer cell antigens and present them to T cells, initiating an adaptive immune response against the cancer.
10. Synergy with Other Immune Cells:
T cells work in synergy with other immune cells, such as natural killer (NK) cells and macrophages, to collectively eliminate cancer cells through a process called immune surveillance.
11. T Cell Trafficking and Homing:
T cells are guided by chemokines and adhesion molecules to migrate to the tumor site, ensuring their presence where they are needed most.
1. Antunes F, Erustes AG, Costa AJ, Nascimento AC, Bincoletto C, Ureshino RP, et al. Autophagy and intermittent fasting: the connection for cancer therapy? Clin Sao Paulo Braz. 2018 Dec 10;73(suppl 1):e814s.
2. Effects of Calorie Restriction on Health Span and Insulin Resistance: Classic Calorie Restriction Diet vs. Ketosis-Inducing Diet - PubMed [Internet]. [cited 2023 Sep 13]. Available from: https://pubmed.ncbi.nlm.nih.gov/33920973/
3. Mihaylova MM, Cheng CW, Cao AQ, Tripathi S, Mana MD, Bauer-Rowe KE, et al. Fasting Activates Fatty Acid Oxidation to Enhance Intestinal Stem Cell Function during Homeostasis and Aging. Cell Stem Cell. 2018 May 3;22(5):769-778.e4.
4. Longo VD, Mattson MP. Fasting: molecular mechanisms and clinical applications. Cell Metab. 2014 Feb 4;19(2):181–92.
5. Effects of Intermittent Fasting on the Circulating Levels and Circadian Rhythms of Hormones - PubMed [Internet]. [cited 2023 Sep 13]. Available from: https://pubmed.ncbi.nlm.nih.gov/34474513/
6. Moro T, Tinsley G, Longo G, Grigoletto D, Bianco A, Ferraris C, et al. Time-restricted eating effects on performance, immune function, and body composition in elite cyclists: a randomized controlled trial. J Int Soc Sports Nutr. 2020 Dec 11;17(1):65.
7. Intermittent fasting protects against food allergy in a murine model via regulating gut microbiota - PubMed [Internet]. [cited 2023 Sep 13]. Available from: https://pubmed.ncbi.nlm.nih.gov/37228621/
8. Jf D, M A, A C, F K, Akl W, Ej van V, et al. Uncovering the mode of action of engineered T cells in patient cancer organoids. Nat Biotechnol [Internet]. 2023 Jan [cited 2023 Sep 14];41(1). Available from: https://pubmed.ncbi.nlm.nih.gov/35879361/
9. Zhou G, Sprengers D, Boor PPC, Doukas M, Schutz H, Mancham S, et al. Antibodies Against Immune Checkpoint Molecules Restore Functions of Tumor-Infiltrating T Cells in Hepatocellular Carcinomas. Gastroenterology. 2017 Oct;153(4):1107-1119.e10.
Reference for autophagy
10.1007/978-1-4614-5915-6_8
1. Autophagy: Intermittent fasting triggers a process called autophagy, where cells break down and remove damaged components. This can be particularly beneficial for T cells because it helps remove dysfunctional or worn-out cellular machinery, keeping T cells more effective and healthy(1).
2. Metabolic Flexibility(ketosis) : During fasting periods, the body switches to using stored fats for energy instead of glucose. T cells are known to be highly adaptable to using these fatty acids and ketones as fuel sources. This metabolic flexibility allows T cells to maintain their function and continue patrolling the body for pathogens even when glucose is scarce(2).
3. Stem Cell Renewal: Intermittent fasting has been shown to stimulate the regeneration of hematopoietic stem cells in the bone marrow. These stem cells are responsible for producing new immune cells, including T cells. Enhanced stem cell activity can lead to the production of more and potentially more potent T cells(3).
4. Reduction in Inflammation: Chronic inflammation can negatively impact T cell function. Intermittent fasting has been associated with a reduction in systemic inflammation, creating a more favorable environment for T cells to operate effectively(4).
5. Hormonal Changes: Fasting can influence the secretion of hormones like insulin and IGF-1. These hormonal changes can impact T cell proliferation and function, potentially enhancing their ability to respond to infections(5,6).
6. Immune Memory: T cells play a crucial role in immunological memory, which allows the immune system to respond more effectively to previously encountered pathogens. Intermittent fasting may support the formation and maintenance of this memory, ensuring a more robust T cell response upon re-exposure to the same threat(7).
MOA OF T-CELL AGAINST CANCER
T cells play a crucial role in the immune system's defense against cancer cells through several mechanisms of action. Here, we'll explore the various ways T cells target and eliminate cancer cells in detail:
1. Direct Cytotoxicity (CD8+ T Cells):
Recognition: Cytotoxic T cells (CD8+) can recognize cancer cells by binding to specific antigens presented on the cancer cell's surface through major histocompatibility complex (MHC) class I molecules. Perforin and Granzymes: Upon recognition, CD8+ T cells release cytotoxic granules containing molecules like perforin and granzymes. Perforin creates pores in the cancer cell membrane, allowing granzymes to enter the cancer cell. Apoptosis: Granzymes trigger apoptosis, a form of programmed cell death, within the cancer cell, leading to its destruction(8).
2. Indirect Cytotoxicity (CD4+ T Cells): Helper Function: CD4+ T cells, also known as helper T cells, indirectly support the cytotoxic activity of CD8+ T cells by releasing cytokines like interferon-gamma (IFN-γ). IFN-γ enhances the ability of CD8+ T cells to kill cancer cells.
3. Memory T Cells:
Long-term Immunity: After an initial encounter with cancer cells, some activated T cells become memory T cells. These memory T cells remain in the body, prepared to respond rapidly if the cancer returns, providing long-term immunity.
4. Checkpoint Inhibition:
Immune Checkpoints: Cancer cells often exploit immune checkpoints, such as PD-1 (programmed cell death protein 1) and CTLA-4 (cytotoxic T-lymphocyte-associated protein 4), to evade T cell attack. Checkpoint Inhibitors: Immunotherapy drugs called checkpoint inhibitors block these checkpoints, "releasing the brakes" on T cells and allowing them to mount a stronger attack against cancer cells(9).
5. CAR-T Cell Therapy (Chimeric Antigen Receptor T Cells):
Engineering T Cells: In CAR-T cell therapy, T cells are genetically engineered to express chimeric antigen receptors (CARs) specific for a particular cancer cell antigen.
Targeting Cancer: These modified T cells can recognize and target cancer cells with precision, enhancing their ability to attack cancer cells.
6. Antigen Recognition and Adaptation:
T Cell Receptors (TCRs): T cells have T cell receptors (TCRs) that are highly specific for antigens. They can adapt and evolve to recognize new cancer cell antigens that may emerge due to mutations or changes in the tumor microenvironment.
7. Tumor-Infiltrating Lymphocytes (TILs):
Infiltrating the Tumor: Some T cells, known as tumor-infiltrating lymphocytes (TILs), migrate into the tumor microenvironment, where they directly engage with cancer cells.
8. Secretion of Cytokines:
Cytokine Release: T cells release various cytokines, including interleukins and tumor necrosis factor (TNF), which can have multiple effects on cancer cells. These cytokines can promote inflammation, recruit other immune cells, and inhibit cancer cell growth.
9. Adaptive Immunity and Antigen Presentation:
Antigen Presentation: Dendritic cells and other antigen-presenting cells capture cancer cell antigens and present them to T cells, initiating an adaptive immune response against the cancer.
10. Synergy with Other Immune Cells:
T cells work in synergy with other immune cells, such as natural killer (NK) cells and macrophages, to collectively eliminate cancer cells through a process called immune surveillance.
11. T Cell Trafficking and Homing:
T cells are guided by chemokines and adhesion molecules to migrate to the tumor site, ensuring their presence where they are needed most.
1. Antunes F, Erustes AG, Costa AJ, Nascimento AC, Bincoletto C, Ureshino RP, et al. Autophagy and intermittent fasting: the connection for cancer therapy? Clin Sao Paulo Braz. 2018 Dec 10;73(suppl 1):e814s.
2. Effects of Calorie Restriction on Health Span and Insulin Resistance: Classic Calorie Restriction Diet vs. Ketosis-Inducing Diet - PubMed [Internet]. [cited 2023 Sep 13]. Available from: https://pubmed.ncbi.nlm.nih.gov/33920973/
3. Mihaylova MM, Cheng CW, Cao AQ, Tripathi S, Mana MD, Bauer-Rowe KE, et al. Fasting Activates Fatty Acid Oxidation to Enhance Intestinal Stem Cell Function during Homeostasis and Aging. Cell Stem Cell. 2018 May 3;22(5):769-778.e4.
4. Longo VD, Mattson MP. Fasting: molecular mechanisms and clinical applications. Cell Metab. 2014 Feb 4;19(2):181–92.
5. Effects of Intermittent Fasting on the Circulating Levels and Circadian Rhythms of Hormones - PubMed [Internet]. [cited 2023 Sep 13]. Available from: https://pubmed.ncbi.nlm.nih.gov/34474513/
6. Moro T, Tinsley G, Longo G, Grigoletto D, Bianco A, Ferraris C, et al. Time-restricted eating effects on performance, immune function, and body composition in elite cyclists: a randomized controlled trial. J Int Soc Sports Nutr. 2020 Dec 11;17(1):65.
7. Intermittent fasting protects against food allergy in a murine model via regulating gut microbiota - PubMed [Internet]. [cited 2023 Sep 13]. Available from: https://pubmed.ncbi.nlm.nih.gov/37228621/
8. Jf D, M A, A C, F K, Akl W, Ej van V, et al. Uncovering the mode of action of engineered T cells in patient cancer organoids. Nat Biotechnol [Internet]. 2023 Jan [cited 2023 Sep 14];41(1). Available from: https://pubmed.ncbi.nlm.nih.gov/35879361/
9. Zhou G, Sprengers D, Boor PPC, Doukas M, Schutz H, Mancham S, et al. Antibodies Against Immune Checkpoint Molecules Restore Functions of Tumor-Infiltrating T Cells in Hepatocellular Carcinomas. Gastroenterology. 2017 Oct;153(4):1107-1119.e10.
Reference for autophagy
10.1007/978-1-4614-5915-6_8
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