Reported by Dr. Liji Thomas, MD, and reviewed by Danielle Ellis, B.Sc. An early trial has shown that a special diet can enhance the activity of immune cells and improve the efficacy of immunotherapy for colorectal cancer patients.
Colorectal cancer ranks third among the causes of cancer deaths worldwide, and the number of deaths is continuously rising. Immune checkpoint inhibitors (ICIs) have shown poor efficacy against these tumors. A recent study in the journal Cell Metabolism explored the impact of a serine/glycine-free diet on tumor growth, especially in relation to immune checkpoint inhibitor therapy.
Immune checkpoint inhibitors have been approved for the treatment of colorectal cancer. However, a group of immunotherapeutic drugs called programmed death-1 (PD-1) inhibitors have relatively low efficacy among colorectal cancer patients.
Only 15% of patients with mismatch repair proficient/microsatellite stable (pMMR/MSS) characteristics benefit from this therapy. In contrast, patients with deficient mismatch repair/microsatellite instability high (d-MMR/MSI-H) colorectal cancer respond well to PD-1 inhibitors, with increased expression of tumor neoantigens and a large infiltration of immune cells into the tumor.
Changing the immune state and the tumor microenvironment is expected to improve the efficacy of immunotherapy. One way to do this is to deprive the tumor of nutrients.
Cancer cells have a very high metabolic rate and continuously consume serine, glycine, and other amino acids throughout their life cycle from occurrence to metastasis. And the supply of these nutrients is also the key to the tumor’s immune evasion.
Cancer cells rely on anaerobic glycolysis to obtain energy and produce a large amount of lactate. High concentrations of lactate can create an immunosuppressive tumor microenvironment, prompting tumor-associated macrophages to shift to the M2 phenotype, reducing the cytotoxicity of CD8+ T lymphocytes and natural killer (NK) cells, and impairing cell-mediated anti-tumor immunity. In addition, lactate can also enhance the activity of regulatory T cells (Treg) within the tumor and regulate anti-tumor immune responses.
Previous studies have explored the impact of a serine/glycine-free diet (-SG diet), but little is known about how it affects the incidence and mortality of colorectal cancer. This has prompted the current study, which focuses on tumor-infiltrating cytotoxic T cells to explore the impact of the -SG diet on the tumor microenvironment in colorectal cancer growth and cell-mediated anti-tumor immunity.
The -SG diet can inhibit the growth of colorectal cancer cells in culture. Its anti-proliferative effect is accompanied by a delay in the entry of the cell cycle into the synthesis phase. Meanwhile, the markers of apoptosis increase, and the number of migrating cells is significantly reduced compared with that of cells grown in a normal medium.
In mouse models, the -SG diet suppresses tumor growth without reducing body weight. Knocking down the serine/glycine transporter did not enhance the tumor suppression effect in this group of mice, but significantly reduced tumor growth in the control group.
The levels of serine and glycine in the blood of mice on the -SG diet decreased, and the proliferation of tumor cells subsequently decreased, which further corroborated the results of in vitro experiments. The increase in large areas of necrosis and apoptosis within the tumor indicates that the anti-tumor effect seems to stem from the enhancement of cell-mediated immune killing.
The -SG diet changes the tumor microenvironment, restarts cell-mediated anti-tumor immune responses, promotes and enhances the diversity and antigen specificity of T cell receptors (TCR), and thus induces a strong T cell response to specific tumor cell epitopes, causing cytotoxic T cells to accumulate in the tumor.
This effect is due to the up-regulated differential expression of lymphocyte differentiation and activation genes in the -SG diet group compared with the control group, and both B-cell- and T-cell-mediated immunity is enhanced. Therefore, the -SG diet exerts its effect by promoting tumor-infiltrating lymphocytes to differentiate into cytotoxic effector CD8+ T cells.
To support this observation, after the depletion of CD8+ T cells, the anti-tumor effect was significantly weakened, and the expression of PD-L1 also decreased significantly. After reinfusion, it increased correspondingly.
Under the pressure of the -SG diet recruiting and activating cytotoxic CD8+ T cells, tumor cells also mutate and express higher levels of immune checkpoint molecules such as PD-1 and its ligand, programmed death ligand 1 (PD-L1), facilitating immune evasion.
Under hypoxic conditions, the increase in lactate concentration promotes the lactylation of PD-L1 within tumor cells, inhibiting its degradation by lysosomes and thereby increasing the level of PD-L1, which constitutes a negative regulatory mechanism.
Therefore, PD-1/PD-L1 inhibitors are needed to maintain a strong anti-tumor immunity. PD-L1 inhibitors work in synergy with the -SG diet to activate cytotoxic CD8+ T cells and enhance the anti-proliferative effect on tumor cells. Compared with the use of anti-PD-1 alone, they can more effectively reduce the volume of colorectal cancer tumors.
It is worth noting that the addition of anti-PD-1 only enhanced the anti-proliferative effect in the control group, but it increased the expression of PD-L1 in the -SG group tumors.
In a single-arm Phase 1 study, the -SG diet has been proven to be feasible and safe as an immunomodulatory measure for colorectal cancer patients.
The serine/glycine-free diet can reduce tumor growth and strengthen the immune-mediated killing of tumor cells by inducing a strong T cell response to tumor neoantigens.
Conversely, this diet promotes immune evasion by inducing PD-L1 lactylation, stabilizing the molecule against lysosomal degradation and enhancing the tumor’s immune evasion ability.
This is a new finding of this study, revealing potential immunotherapy targets, such as the increased PD-L1 on tumor cells. Tumor metabolism or neoantigen expression is also a target that can increase the tumor’s susceptibility to immune-mediated killing.
In addition, the Phase 1 clinical trial has demonstrated the safety and feasibility of the serine/glycine-free diet, which has the potential to be combined with immunotherapy for solid colorectal cancers.
These findings have expanded previous studies on the SG diet, showing its impact on the tumor microenvironment, T cell recruitment, and the induction of the T cell cytotoxicity phenotype.
Different from most previous studies and the authors’ in vitro experiment results, regarding the increase in CD8+ T cell activation and infiltration observed with the -SG diet, based on the impact of this diet and lactate on tumor cells, the authors have provided several explanations for this paradox.
Larger-scale trials are still needed to verify these results, which may discover promising treatment methods for solid tumors.
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