Summary:

Metabolic features of both cancer cells and immune cells shift with nutrient availability in the tumor microenvironment, resulting in differential effects on antitumor immune function. The work of Fischer and colleagues demonstrates that increased oxidative phosphorylation in brain metastases in patients with melanoma is a key regulator of intracranial immune surveillance and that inhibition of oxidative phosphorylation could reduce the incidence of intracranial brain metastases in a murine model of melanoma.

See related article by Fischer et al., p. 628.

Differential energy metabolism by cancer cells was famously first described as a shift from oxidative phosphorylation (OXPHOS) to glycolysis. This well-known “Warburg effect” has recently resurfaced in light of understanding a complex and competitive interplay between immune cells and cancer cells in the tumor microenvironment. Cancer cells, in a heavily proliferative and increased glycolytic state, have been demonstrated to outcompete immune effector cells for available glucose (1). It is now becoming clear that, in addition to increased glycolysis, increased OXPHOS by cancer cells and the resulting oxygen deprivation (hypoxia) in the tumor microenvironment has a significant detrimental impact on immune cell function. Thus, immune cells such as effector T cells have reduced functional capacity in the tumor microenvironment directly as a result of depleted nutrient ability and a resulting environmental metabolic checkpoint. Ramifications of such metabolic competition in the tumor microenvironment have attracted attention for potential therapeutic intervention in combination with immunotherapies, such as checkpoint blockade.

In this issue, Fischer and colleagues demonstrate that melanoma brain metastases could be segregated by gene-expression analysis into two distinct types: immune enriched and immune deficient (2). As expected, patient survival was greater in patients with immune-enriched brain metastases. Of interest, however, was that immune enrichment did not correlate with current “likely suspects” for driving immune activity, such as increased mutation load, increased PTEN alterations, or decreased B-catenin levels. Surprisingly, then, the major correlate with upregulated immune-deficient brain metastases was found to be an increase in OXPHOS pathways. Impressively, the inhibition of OXPHOS activity demonstrated increased survival in both murine tumor implantation models and spontaneous models of brain metastases. Intriguingly, OXPHOS inhibition specifically resulted in reduced brain metastasis incidence, as primary tumor growth and lung metastasis incidence were not changed.

Melanoma brain metastases have recently been demonstrated to be responsive to checkpoint blockade with a similar response rate to extracranial metastases. However, Fischer and colleagues demonstrate that in matched intracranial and extracranial metastatic samples, intracranial metastases have fewer CD3+ T cells, CD8+ cells, dendritic cells, and monocytic cells. Similarities in their incidences of PTEN alterations, β-catenin levels, and mutation loads between intracranial and extracranial samples suggest that the intrinsic molecular characteristics of melanoma cells responsible for brain metastasis do not in themselves confer reduced immunogenicity. This observation was elegantly supported by the authors' demonstration that cell lines injected intracranially and subcutaneously had a divergent metabolic profile with increased levels of OXPHOS metabolites in the intracranial implants. Together, these data clearly identify increased oxidative activity in melanoma brain metastases as an important process that interferes with potential brain-localized antitumor immune responses.

Further studies to explore mechanisms for the association between increased tumor OXPHOS and increased immune suppression are warranted. Certainly, T cells have been shown to exhibit a dysfunctional metabolic profile, such as decreased mitochondrial biogenesis, in the tumor microenvironment (3). Thus, cancer cell depletion of available oxygen coupled with T-cell inherent metabolic dysfunction may have significant effects on T-cell antitumor potential. Although oxygen metabolism in T-cell effector function is less critical, memory formation and perhaps proliferation do require oxygen metabolism (4). Fischer and colleagues' observation that brain metastases had decreased numbers of T cells may therefore reflect a hindrance of local expansion due to metabolic dysregulation. However, reduced levels of dendritic cells and monocytic cells suggest tumor trafficking may also play a role. Certainly, effects of hypoxia-related irregular vasculature formation and integrity may play a key role in immune trafficking to metastatic sites. How hypoxic conditions interplay with TGFβ signaling, now well accepted to promote T-cell exclusion from tumor beds, merits exploration in future studies of brain metastases (5). Finally, effects of hypoxic conditions on regulatory immune cell composition, either function or frequency, in the tumor microenvironment of brain metastases would be of interest in future studies.

Previous preclinical studies demonstrated the efficacy of OXPHOS modulation in MAPK inhibitor–resistant cell lines using mTORC1/2 inhibitors (6). Additionally, other preclinical studies observed increased intratumoral T-cell numbers and tumor clearance with a combination of anti–PD-1 antibodies and metformin, a mitochondrial OXPHOS inhibitor (7). Concurrent studies by Najjar and colleagues revealed that anti–PD-1 resistance both in preclinical melanoma models and from melanoma patient samples is tightly linked to oxygen metabolism in tumor tissues (8). Intriguingly, Fischer and colleagues also identified increased levels of intratumoral immune cells in brain metastases with prior radiotherapy. Evidence for targeting unique properties of intracranial melanoma metastases, such as AKT hyperactivation and activated STAT3, is increasingly apparent (9, 10). Together, these studies suggest an opportunity for creative treatments of melanoma brain metastases using combinations of targeted therapies, radiation, checkpoint blockade, and OXPHOS inhibitors (metformin, mTORC1/2 inhibitors, etc.; Fig. 1).

Key questions that remain are: (i) How do unique metabolic features of brain metastases coupled with unique immune trafficking patterns to brain metastases affect immune cell function and composition? (ii) How do unique metabolic features of melanoma brain metastases mechanistically alter responses to checkpoint blockade? (iii) What is the role of increased hypoxia and decreased oxygen availability on antigen-presenting cell availability and function? (iv) What is the correct sequencing for complex therapeutic combinations including OXPHOS inhibitors and checkpoint blockade? (v) How do immune responses to intracranial and extracranial metastases concert together for an effective relapse-free outcome of patients with melanoma?

Three major implications of the work of Fischer and colleagues are that (i) OXPHOS dependency of brain metastases is druggable, and future clinical trials should address combinatorial OXPHOS inhibition with various immunotherapy targets, keeping in mind the importance of studying the impact of these interventions on immune-mediated and molecularly targeted mechanisms of melanoma eradication, which may also be adversely affected by the same therapeutic approach; (ii) brain metastases are metabolically unique and need further research to interrogate mechanisms of intrinsic and acquired immunotherapeutic resistance; and (iii) treatment of patients with melanoma with multiple organ metastases may require a multipronged approach in which different organ metastases require different intervention strategies to ensure complete responses required for long-term control and potential curative outcomes for patients with advanced melanoma.

K. Margolin is a consultant/advisory board member for Iovance, ImaginAb, Guidepoint, and Nektar. No potential conflicts of interest were disclosed by the other author.

1.
Chang
CH
,
Qiu
J
,
O'Sullivan
D
,
Buck
MD
,
Noguchi
T
,
Curtis
JD
, et al
Metabolic competition in the tumor microenvironment is a driver of cancer progression
.
Cell
2015
;
162
:
1229
41
.
2.
Fischer
GM
,
Jalali
A
,
Kircher
DA
,
Lee
W-C
,
McQuade
JL
,
Haydu
LE
, et al
Molecular profiling reveals unique immune and metabolic features of melanoma brain metastases
.
Cancer Discov
2019
;
9
:
628
45
.
3.
Scharping
NE
,
Menk
AV
,
Moreci
RS
,
Whetstone
RD
,
Dadey
RE
,
Watkins
SC
, et al
The tumor microenvironment represses T cell mitochondrial biogenesis to drive intratumoral T cell metabolic insufficiency and dysfunction
.
Immunity
2016
;
45
:
374
88
.
4.
van der Windt
GJ
,
Everts
B
,
Chang
CH
,
Curtis
JD
,
Freitas
TC
,
Amiel
E
, et al
Mitochondrial respiratory capacity is a critical regulator of CD8+ T cell memory development
.
Immunity
2012
;
36
:
68
78
.
5.
Mariathasan
S
,
Turley
SJ
,
Nickles
D
,
Castiglioni
A
,
Yuen
K
,
Wang
Y
, et al
TGFbeta attenuates tumour response to PD-L1 blockade by contributing to exclusion of T cells
.
Nature
2018
;
554
:
544
8
.
6.
Gopal
YN
,
Rizos
H
,
Chen
G
,
Deng
W
,
Frederick
DT
,
Cooper
ZA
, et al
Inhibition of mTORC1/2 overcomes resistance to MAPK pathway inhibitors mediated by PGC1alpha and oxidative phosphorylation in melanoma
.
Cancer Res
2014
;
74
:
7037
47
.
7.
Scharping
NE
,
Menk
AV
,
Whetstone
RD
,
Zeng
X
,
Delgoffe
GM
. 
Efficacy of PD-1 blockade is potentiated by metformin-induced reduction of tumor hypoxia
.
Cancer Immunol Res
2017
;
5
:
9
16
.
8.
Najjar
YG
,
Menk
AV
,
Sander
C
,
Rao
U
,
Karunamurthy
A
,
Bhatia
R
, et al
Tumor cell oxidative metabolism as a barrier to PD-1 blockade immunotherapy in melanoma
.
JCI Insight
2019
;
4
(5):
e124989
.
9.
Priego
N
,
Zhu
L
,
Monteiro
C
,
Mulders
M
,
Wasilewski
D
,
Bindeman
W
, et al
STAT3 labels a subpopulation of reactive astrocytes required for brain metastasis
.
Nat Med
2018
;
24
:
1024
35
.
10.
Niessner
H
,
Forschner
A
,
Klumpp
B
,
Honegger
JB
,
Witte
M
,
Bornemann
A
, et al
Targeting hyperactivation of the AKT survival pathway to overcome therapy resistance of melanoma brain metastases
.
Cancer Med
2013
;
2
:
76
85
.