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Laubach et al. Cancer Drug Resist 2023;6:611-41 https://dx.doi.org/10.20517/cdr.2023.60 Page 613

towards the Warburg effect in malignant cells generates high levels of lactic acid, while consuming and
producing ATP/adenosine diphosphate (ADP) and oxidizing and reducing nicotinamide adenine
+
dinucleotide (NAD). While concurrently studying lactate, adenosine, and NAD in the context of energy
metabolism is important, each individual metabolite uniquely influences the function of malignant and
immune cells within the TIME. Therefore, this section will focus on how the altered metabolism of lactate,
+
+
adenosine, and NAD by tumor cells impacts the anti-tumor immune response by CD8 T cells and
contributes to anti-PD-1/PD-L1 resistance.
Lactate
Lactate is predominantly formed through glycolysis, wherein lactate dehydrogenase (LDH) reduces
pyruvate to lactic acid, which then dissociates into hydrogen (H ) and lactate ions [Figure 1]. To a lesser
+
extent, glutaminolysis also drives pyruvate formation, resulting in lactic acid production . Lactate and H
+
[11]
are exported through proton-linked monocarboxylate transporters 1-4 (MCT1-4) , wherein export is
[12]
highly dependent on the existing concentration of extracellular lactate . Intracellular lactate levels are also
[13]
modulated by import through MCT1 . Extracellular lactate facilitates intracellular signaling by binding to
[14]
hydroxycarboxylic acid receptor 1 (HCAR1), which regulates a variety of downstream oncogenic pathways,
such as cell proliferation, migration, and invasion . Accumulation of H via lactic acid production
+
[15]
[16]
contributes to the acidity of the TIME, which promotes an immunosuppressive milieu . Conversely,
lactate ions have both tumor-promoting and -inhibiting effects in CD8 T cells.
+
T cells require adequate levels of lactic acid for proper development and function [17,18] , but excess amounts in
the TIME and intracellularly promote dysfunction. Tumor-derived lactic acid accumulation within the
[19]
TIME inhibits T cell proliferation and cytokine production by altering redox homeostasis . Specifically,
lactic acid downregulates T cell production of both reactive oxygen species (ROS) and the antioxidant
glutathione . While excess amounts of ROS promote oxidative stress, low levels are important for T cell
[19]
activation and signaling , suggesting that tumor-derived lactic acid inhibits T cell functions by ablating
[20]
ROS formation. Additionally, overabundance of lactic acid in the TIME prevents T cell export of lactate and
H ions because of the unfavorable concentration gradient, and subsequent accumulation promotes
+
intracellular acidification and decreases effector function . In particular, intracellular acidification in T
[21]
cells due to tumor-derived lactic acid production prevents the expression of nuclear factor of activated T
+
cells (NFAT) , a family of transcription factors that mediate T cell development . In CD8 T cells,
[23]
[22]
decreased NFATC1 expression reduces IFNg production, whereas inhibiting lactate dehydrogenase A
[22]
+
(LDHA) reduces intracellular acidification and restores CD8 T cell function and tumor infiltration .
Similarly, the hypoxic nature of the TIME drives upregulation of LDHA in CD8 tumor-infiltrating
+
lymphocytes (TILs), leading to excess intracellular lactic acid, which then inhibits IFNg and granzyme B
production and T cell expansion . Upon chronic antigen stimulation, CD8 T cells will progress through
+
[18]
[24]
progenitor exhausted and terminally exhausted states, with the latter resulting in dysfunction and the
inability to elicit anti-tumor effects . Therefore, there has been a significant focus on promoting the
[25]
expansion of non-exhausted states and inhibiting the progression into terminal exhaustion to reinvigorate
the anti-tumor response. Researchers found that treatment of CD8 T cells with IL-21 promotes expansion
+
but does not drive T cells towards an exhausted state, like IL-2 . Moreover, IL-2, but not IL-21, induced
[18]
metabolic reprogramming in T cells to favor glycolysis and shunt pyruvate towards lactic acid formation .
[18]
Treatment with IL-2 and LDH inhibitor invoked a shift from glycolysis towards oxidative phosphorylation,
and IL-2 or IL-21 treatment in combination with LDH inhibitor increased stem cell memory T cell
formation and reduced tumor growth . These data demonstrate that tumor-derived lactic acid can directly
[18]
or indirectly inhibit T cell function and anti-tumor immune response.