What is the harmful metabolites of TME in anti-tumor immunity?

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What is the harmful metabolites of TME in anti-tumor immunity?

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What is the harmful metabolites of TME (Tumor Microenvironment) in anti-tumor immunity?

Cancer immunotherapy has revolutionized the approach to treating cancer, opening the door to durable disease-free states for some patients.

With this significant advancement, there is a deeper understanding of the interplay between the immune system and cancer and the major obstacles hindering successful antitumor immunity.

One such obstacle is the harsh metabolic environment within the tumor microenvironment (TME).

It is well-known that disrupted metabolism in cancer cells leads to an environment characterized by hypoxia, acidity, glucose, and amino acid deficiencies.

Many tumors undergo “Warburg metabolism” or aerobic glycolysis.

Additionally, rapid proliferation and abnormal cell signaling result in inadequate vasculature within the TME, leading to poor oxygenation.

The metabolites generated during these processes are crucial for shaping immune cell function and their response to immunotherapy.

Therefore, we can no longer rely on a simplistic model of starving immune cells within tumors. Instead, we must consider the impact of “toxic” breakdown metabolites generated during immune cell function. Metabolites like lactate, kynurenine, adenosine, and reactive oxygen species (ROS) are commonly found in various tissues and immune environments, and it is these non-tumor environments that have shaped immune cells throughout evolution. Thus, it is important to view the TME as one of many metabolic environments for immune cells and seek metabolic insights from non-tumor environments concerning tumor-infiltrating lymphocytes. This perspective is crucial for implementing metabolic strategies to improve immunotherapy, as it will elucidate how these treatments may affect the immune system.

Lactate

In the TME, lactate is produced by highly glycolytic tumor cells, which ferment glucose to pyruvate and then convert it to lactate via lactate dehydrogenase (LDH). In normal serum, lactate concentrations range from 1.5 to 3 mM, while in tumors, they range from 10 to 30 mM, reaching extremely high levels (50 mM) within necrotic tumor cores.

Increased lactate levels are associated with poor prognosis in several cancer types. Lactate, as an immunosuppressive metabolite, reduces the proliferation and cytokine production capacity of CD8+ and CD4+ T cells when exposed to lactate concentrations equivalent to those in the tumor. Lactate restricts T cell proliferation by altering the NAD(H) redox state, reducing NAD+ to NADH under lactate-rich conditions, thereby affecting NAD+-dependent enzymatic reactions required for glycolysis intermediates necessary for proliferation.

Not all immune cells respond negatively to tumor-derived lactate. The TME actively recruits and promotes the differentiation of Tregs, effective immunosuppressors responsible for maintaining immune homeostasis and preventing autoimmunity. Unlike effector cells, Tregs do not rely heavily on glycolysis for metabolic requirements but rather depend on oxidative metabolism, including lipid synthesis and signaling. This enables Tregs to thrive and exert their immunosuppressive function in glucose-depleted TME. Lactate is crucial for the proliferation and function of tumor-infiltrating Tregs compared to effector T cells.

Lactate also influences innate immune cells. It has been found to polarize macrophages toward an M2-like TAM state, including increased arginase-1 (Arg1) expression. One potential mechanism by which lactate may affect macrophage and Treg function is through its contribution to histone lactylation, a histone modification distinct from acetylation with pronounced dynamic characteristics.

Kynurenine

Another metabolite consistently upregulated in various cancer types is kynurenine. Similar to lactate, kynurenine is an immunosuppressive byproduct, originating from the consumption of the essential metabolite tryptophan. The consumption of tryptophan and the generation of kynurenine are driven by three rate-limiting enzymes, namely indoleamine 2,3-dioxygenase 1 (IDO1), IDO2, and tryptophan 2,3-dioxygenase (TDO). IDO1 is expressed by various cell types, including immune cells, epithelial cells, cancer cells, and fibroblasts. IFN-γ produced during tissue inflammation greatly enhances IDO1 expression and serves as a negative feedback loop to suppress excessive inflammation.

Similar to glucose and lactate, tryptophan depletion and kynurenine production have independent immunosuppressive effects. Kynurenine can inhibit immune responses by promoting tolerogenic antigen-presenting cell differentiation, fostering Treg differentiation via the aryl hydrocarbon receptor (AhR), and inhibiting IL-2 signaling.

IDO1 is expressed in many tumor types, and high expression is associated with poor prognosis and increased tumor-infiltrating Tregs. Kynurenine can also directly impact effector T cells, as T cell receptor (TCR) stimulation increases kynurenine uptake through Slc7a5/Slc7a8, leading to increased AhR-induced PD-1 expression.

In summary, tryptophan depletion and kynurenine production create an immunosuppressive environment that maintains immune tolerance under steady-state conditions but is exploited by tumors to evade immune destruction.

Reactive Oxygen Species (ROS)

Many tumors experience varying degrees of hypoxia. When the low vascularity and high metabolic demands of tumors exceed the available oxygen supply, oxygen consumption occurs. Like glucose and tryptophan consumption, oxygen consumption is accompanied by the generation of toxic byproducts such as reactive oxygen species (ROS) and adenosine, which has been a focal point of cancer research.

ROS, as a normal part of oxidative metabolism, are vital for the survival, signaling, and homeostasis of normal cells. However, cancer exploits ROS, using their overproduction to drive mitotic signaling pathways, metastasis, and survival. In addition to ROS, tumor hypoxia also leads to the accumulation of extracellular ATP, which is converted to the immunosuppressive metabolite adenosine. ATP release and adenosine generation act on purinergic receptors, impairing immune cell infiltration and activation, thus reducing antitumor immunity.

Similar to lactate and kynurenine, ROS play a crucial role in shaping immune cell function in non-tumor environments. ROS can also participate in chemotaxis, signaling to neutrophils and other immune cells, guiding them to sites of damage or infection and even activating dendritic cells.

However, high levels of ROS impair effector T cells within the TME. Increased oxidative stress in the TME is associated with CD8+ T cell exhaustion and reduced responsiveness to anti-PD-1 immunotherapy. Recent mechanistic studies suggest that sustained TCR stimulation and hypoxia induce increased mitochondrial ROS production in CD8+ T cells, enough to induce an exhausted-like phenotype. In addition to impairing effector cells, high levels of ROS can support regulatory cell populations, such as TAMs and MDSCs.

In summary, while low levels of ROS are critical for normal immune function, high levels of ROS within the TME promote functional impairment of effector cells and the presence of regulatory cell populations.

Adenosine

Adenosine is an effective immunosuppressive metabolite, damaging effector cells while supporting regulatory cells. Within the TME, ad

enosine is generated through the action of cell-surface ectonucleotidases CD39 and CD73, expressed by tumor cells and infiltrating immune cells. Hypoxia drives the activity of HIF1A, which upregulates CD39, CD73, and adenosine receptor A2BR. Extracellular ATP is converted to ADP and/or AMP by CD39, and AMP is subsequently converted to adenosine by CD73. Adenosine then binds to one of four receptors—A1R, A2AR, A2BR, or A3R—to exert its immunosuppressive effects. Signaling through A2AR and A2BR can reduce IFN-γ and IL-2 production, increase inhibitory molecule PD-1 in effector cells, and activate Foxp3, CTLA4, and Lag-3, promoting Treg development.

Targeted Therapies for Harmful Metabolites

Understanding the production and immunoregulatory effects of lactate, kynurenine, ROS, and adenosine has led to the development of therapies aimed at improving cancer immunotherapy.

Altering Tumor Metabolism

There are various strategies to modify tumor metabolism. For instance, lactate production can be reduced by inhibiting lactate dehydrogenase. Studies with the inhibitor GSK2837808A showed enhanced T cell killing in vitro and in vivo when LDHA, the lactate-producing enzyme, was inhibited in patient-derived and B16 melanoma LDHA. While specific LDH and glycolysis inhibitors have not yet fully entered clinical trials, there is potential to repurpose existing drugs with glycolysis-inhibiting effects. For example, diclofenac, a common nonsteroidal anti-inflammatory drug, has been shown to regulate glycolysis independently of COX inhibition and can be used to enhance anti-PD-1 immunotherapy.

Lactate levels in the TME can also be reduced by targeting its efflux. Lactate is transported through monocarboxylate transporters (MCTs), and while many small molecule inhibitors of MCT1 and MCT4 have been developed for preclinical purposes, only AstraZeneca’s AZD3965 is undergoing human trials (NCT01791595). Preclinical studies have shown that AZD3965 can reduce lactate secretion into the TME and increase tumor-infiltrating immune cells.

Most research targeting kynurenine has focused on inhibiting IDO1. Currently, several IDO inhibitors are in clinical trials (NCT04049669, NCT03432676, NCT02471846). Unfortunately, the trial of Incyte’s epacadostat in combination with pembrolizumab was terminated after mid-stage analysis showed no additional benefit (NCT03432676). This setback certainly dampened enthusiasm for IDO1 targeting, but it underscores the complexity of the IDO pathway, which may require a certain degree of tryptophan degradation metabolism to produce the optimal immunoregulatory antitumor response.

Due to the diversity in mechanisms of ROS production, there are multiple ways to target tumor-derived ROS. One promising approach is to reduce tumor hypoxia. In preclinical models, metformin, a weak mitochondrial complex I inhibitor, when used in combination with anti-PD-1, reduces tumor hypoxia and promotes B16 tumor clearance. Targeting tumor hypoxia can also be achieved by inhibiting VEGF. Clinically, the combination of anti-angiogenesis and immunotherapy has shown the greatest efficacy in renal cell carcinoma (RCC) and hepatocellular carcinoma (HCC), with atezolizumab and bevacizumab combination therapy improving progression-free survival and overall survival.

Another approach to target tumor-derived ROS is to use scavengers. For example, the drug RTA-408, which induces Nrf2, a key protein involved in oxidative stress protection, has been shown to inhibit ROS in a murine heterotransplant model. In 2019, a phase Ib/II clinical trial combining anti-CTLA-4 and anti-PD-1 with RTA-408 was completed in melanoma patients, but results have not been formally disclosed (NCT02259231).

In addition to the aforementioned strategies, there are direct approaches to inhibit adenosine production. These drugs appear as small molecule inhibitors or blocking antibodies targeting CD73, CD39, and A2AR. While these drugs have demonstrated preclinical efficacy in reducing adenosine production and even preventing soluble CD73’s ectonucleotidase activity, most are awaiting results from phase I/II clinical trials.

Modifying Infiltrating Immune Cell Metabolism

CAR-T and other adoptive T-cell therapies provide a means of metabolic support for T-cells to function effectively within the harsh tumor microenvironment (TME). One approach to enhancing CAR-T cells involves overexpressing or deleting genes that regulate metabolism. For instance, in adoptive cell therapy models, overexpression of PGC1α (a transcription coactivator for mitochondrial biogenesis) prevents mitochondrial dysfunction and enhances anti-tumor efficacy. Conversely, the loss of the Regnase-1 gene increases the efficiency of adoptive cell transfer. The Regnase-1 gene is thought to negatively regulate transcription factors BATF and mitochondrial metabolism in CD8+ T-cells.

Metabolic support for adoptive T-cell therapy can also be achieved through the choice of expansion media. Common culture media such as RPMI, DMEM, and AIM V contain high levels of glucose and lower levels of metabolic byproducts, inadequately preparing T-cells for the harsh metabolic environment of tumors. Since T-cells are highly sensitive to their metabolic surroundings, amplifying T-cells in media with specific metabolic components, or the absence thereof, may enhance their persistence and efficacy in vivo. Accordingly, limiting glutamine by nutrient deprivation or metabolic inhibitors in vitro has been shown to enhance the efficacy of adoptive transfer T-cells in mice. Restricting metabolic byproducts or adding metabolic inhibitors to expansion media is an attractive strategy for improving adoptive cell therapy.

Summary

Tumors not only consume essential metabolites but also continuously produce toxic byproducts that persist in the TME. The consumption of metabolic byproducts like glucose, amino acids, and oxygen, along with the production of lactate, kynurenine, reactive oxygen species, and adenosine, all negatively regulate effector immune cells while supporting regulatory immune populations.

As we delve further into the immunometabolism of the TME, understanding the independent impacts of metabolite consumption and production on immune cell function becomes crucial. There may be a more delicate balance than initially thought between the consumption of essential metabolites and the production of toxic metabolites, as seen in the failed trials of IDO1 inhibitors. Ultimately, comprehending the physiological balance between essential metabolites and their toxic byproducts and their subsequent effects on immune cells will be key in developing cancer treatment strategies.

What is the harmful metabolites of TME in anti-tumor immunity?

Reference:
1. Fighting in a wasteland: deleterious metabolites and antitumor immunity. J Clin Invest. 2022 Jan 18; 132(2):e148549.

(source:internet, reference only)

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