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Page 620 Laubach et al. Cancer Drug Resist 2023;6:611-41 https://dx.doi.org/10.20517/cdr.2023.60

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In immune cells, CD38 is inversely correlated with NAD levels because it degrades NAD to NAM and
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ADP-ribose [108,109] . These derivates of NAD are important secondary messengers that regulate intracellular
[109]
calcium levels and storage, which in turn mediates T cell differentiation and activation . CD38 expression
is a marker of T cell exhaustion that contributes to adverse epigenetic modifications in CD8 TILs .
[110]
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Further, high expression of CD38, PD-1, and CD101 correlates with the inability of CD8 T cells to undergo
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epigenetic reprogramming to reverse the exhausted state . Conversely, inhibiting CD38 expression in
[110]
Tregs and B-regulatory cells induced cell death, but drove proliferation of cytotoxic T cells, likely due to
depletion of the immunosuppressive populations . Consistently, mice deficient in CD38 expression
[111]
[106]
exhibited lower Treg numbers as a result of increased NAD levels . CD38 expression on tumor cells has
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also been implicated in a variety of solid and hematologic malignancies [112-116] . Increased CD38 expression on
malignant cells results in acquired resistance to anti-PD-1/PD-L1 therapy by driving CD8 T cells towards
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an exhausted state . Moreover, CD8 T cell function was found to be inhibited by CD38-mediated
[114]
adenosine production, and anti-PD-L1 and CD38 combination therapy synergistically inhibited the growth
of murine lung adenocarcinoma tumors . Currently, there are two approved anti-CD38 monoclonal
[114]
antibody treatments (Daratumumab and Isatuximab) and one in clinical trials (MOR202) to treat multiple
myeloma; however, these drugs do not inhibit the ectoenzymatic activity of CD38, rather they induce
antibody-dependent cell-mediated cytotoxicity [117-119] . There are several drugs in pre-clinical stages that
target the ectoenzymatic activity of CD38 to increase NAD levels for different diseases [120-122] . While these
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drugs are not yet being evaluated in the oncologic space, it would be advantageous because inhibiting CD38
is both beneficial for T cells and detrimental for malignant and immunosuppressive cells, thus eliminating
the need for cell-specific drugs.
Taken together, these data demonstrate an important role for lactate, adenosine, and NAD in regulating
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immune cell function and ultimately controlling cancer development and progression. Further, pre-clinical
studies show promising results that combining these treatments with existing ICB therapies can remodel the
TIME to boost the anti-tumor immune response. Thus, continued pre-clinical and clinical efforts are
needed to determine whether resistance to anti-PD-1/PD-L1 therapy is ablated when combined with
approved anti-CD39/CD73/A2AR/CD38 treatments.

AMINO ACID METABOLISM
Amino acid metabolism is widely implicated in oncogenesis due to the necessity of amino acids in protein
synthesis, epigenetic modifications, and fueling energetic processes. Of the 20 amino acids, only a handful
are well-studied in the context of immuno-oncology metabolism and resistance to ICB. Because tryptophan
[123]
is thoroughly researched in this space and was recently comprehensively reviewed , we wanted to focus
on amino acids that are sometimes overlooked but still immensely important in regulating cancer
development and progression. As such, this section will discuss how tumor-derived alterations in arginine,
glutamine, and methionine metabolism contribute to anti-tumor immunity and how modifying the
metabolism of these amino acids helps diminish resistance to anti-PD-1/PD-L1 therapy.

Arginine
Arginine is considered a non-essential amino acid in normal cells because it can be imported or synthesized
through citrulline metabolism in the urea cycle [Figure 2]. Conversely, arginine is also catabolized
[124]
through the urea cycle to form urea and ornithine through arginase (ARG) enzymes . Extracellular
[124]
arginine also participates in the activation of intracellular signaling pathways by binding to G protein-
coupled receptor family C group 6 member A (GPRC6A) . While arginine itself is important for many
[125]