Androgen deprivation therapy (ADT) is the front-line treatment for early and metastatic prostate cancer, and the development of tumor resistance to it has major clinical consequences. Cancer cells start to proliferate and tumors begin to regrow, requiring the administration of more generic anticancer treatments like surgery, radiotherapy, and/or chemotherapy. Tumor-associated macrophages are known to drive tumor resistance to a number of anti-cancer therapies. El-Kenawi and colleagues now demonstrate a novel mechanism underpinning their ability to do so in prostate tumors during ADT. This involves the accumulation of cholesterol by macrophages in tumors and its transfer to cancer cells, where it acts as a precursor for androgen biosynthesis and results in the activation of androgen receptors.

See related article by El-Kenawi and colleagues, p. 5477

Androgens stimulate the progression of prostate cancer by activating androgen receptors (AR) in cancer cells. This discovery prompted the development of various forms of androgen deprivation therapy (ADT), which reduce either the production of androgens by the testes (e.g., the GnRH inhibitor, Lupron) or AR signaling in prostate cancer cells (e.g., the AR antagonist, enzalutamide). Although both forms of ADT are highly effective, within 2 to 3 years, some tumors develop resistance to ADT and become castration-resistant prostate cancers (CRPC).

Considerable effort has focused on identifying the cellular events leading to this form of resistance. ARs are known to be present throughout the course of the disease, and dysregulated AR signaling occurs in prostate cancer cells in CRPC. However, an important role for macrophages in resistance to ADT is emerging. ADT is known to cause major changes in the immune landscape of prostate tumors including increased infiltration by CD4+ and CD8+ T cells as well as tumor-associated macrophages (TAM; ref. 1). Furthermore, elevated numbers of TAMs in ADT-treated tumors correlate with treatment failure and recurrence (2).

In the current study, El-Kenawi and colleagues (3) use a new, clinically relevant mouse prostate cancer model, human prostate tumor explants, and macrophage/cancer cell cocultures to show that macrophages can take up cholesterol in the form of low-density lipoprotein (LDL) and shuttle it to prostate cancer cells to support their synthesis of androgen. Macrophages were also shown to be able to stimulate AR translocation to the nucleus in prostate cancer cells in cocultures. Furthermore, they demonstrated that macrophage abundance correlated with ADT resistance in patient-derived explants and that macrophage depletion in mice (using a CSF1 neutralizing antibody) reduced both tumor androgen levels and various surrogates of AR activation, as well as extending survival after ADT.

It is tempting to link these findings to a recent report showing that the effects of ADT were improved in patients taking statins, agents known to reduce systemic cholesterol levels (4). This would likely decrease the availability of circulating cholesterol for uptake by TAMs during ADT and its transfer to cancer cells. This would then limit intratumoral androgen biosynthesis and possibly delay the onset of CRPC.

Although the subcellular mechanism(s) mediating the transfer of cholesterol between macrophages and cancer cells have yet to be identified, the authors show that it can be limited using an agonist of an intracellular protein called liver X receptor β (LXRβ). This is one of two isoforms (α and β) of LXR, transcription factors known to limit lipid overloading in macrophages by regulating cholesterol metabolism and efflux pathways. The authors showed that the potent LXRβ agonist, RGX-104, reduced both LDL uptake by macrophages and their ability to stimulate nuclear AR translocation in neighboring cancer cells—an event known to occur after androgen binding/activation of ARs. It remains to be seen whether ADT alters the expression or function of LXRβ but, if so, it could have a major effect on the tumor microenvironment. For example, a recent study showed that LXR-deficient macrophages are defective in their clearance of apoptotic cancer cells in ADT-treated mouse prostate tumors, which in turn led to increased tumor inflammation and proliferation of cancer cells (5).

It also remains to be seen whether TAM behavior is altered by their changes in cholesterol metabolism during ADT and/or the associated increase in local androgen levels (as macrophages are known to express ARs; ref. 6). Interestingly, prostate cancer cells express increased SEMA3A during ADT, which recruits monocytes into tumors and skews them toward a tumor-promoting (i.e., “M2-like”) phenotype capable of promoting ADT resistance. These effects are mediated by the SEMA3A receptor, neuropilin-1 (NRP-1), on TAMs (7). As NRP-1 contributes to lipid uptake by other cell types (8), it may also promote this during ADT. It would be interesting to see whether cholesterol-laden TAMs during ADT express NRP-1 and an M2-like activation state. If so, it may contribute to the observation that blocking the SEMA3A/NRP1 axis reversed ADT resistance in mice (7).

The authors concluded that the therapeutic targeting of TAMs in prostate tumors might delay the onset of CRPC. But attempts to generally deplete macrophages in patients with cancer have been unsuccessful in clinical trials, largely due to severe, off-target side effects (9). A subset of TAMs has been shown to drive resistance to chemotherapy, radiotherapy, and immunotherapy in other forms of cancer (10). If this also proves to be the case for ADT resistance, then it may be possible to selectively target this subpopulation, leaving macrophages in healthy tissues unaffected.

No disclosures were reported.

The work of the authors in this area is supported by Prostate Cancer-UK.

1.
Gannon
PO
,
Poisson
AO
,
Delvoye
N
,
Lapointe
R
,
Mes-Masson
A-M
,
Saad
F
. 
Characterization of the intra-prostatic immune cell infiltration in androgen-deprived prostate cancer patients
.
J Immunol Methods
2009
;
348
:
9
17
.
2.
Nonomura
N
,
Takayama
H
,
Nakayama
M
,
Nakai
Y
,
Kawashima
A
,
Mukai
M
, et al
Infiltration of tumor-associated macrophages in prostate biopsy specimens is predictive of disease progression after hormonal therapy for prostate cancer
.
BJU Int
2011
;
107
:
1918
22
.
3.
El-Kenawi
A
,
Dominguez-Viqueira
W
,
Liu
M
,
Awasthi
S
,
Abraham-Miranda
J
,
Keske
A
, et al
Macrophage-derived cholesterol contributes to therapeutic resistance in prostate cancer
.
Cancer Res
2021
;
81
:
5477
90
.
4.
Peltomaa
AI
,
Raittinen
P
,
Talala
K
,
Taari
K
,
Tammela
TLJ
,
Auvinen
A
, et al
Prostate cancer prognosis after initiation of androgen deprivation therapy among statin users. a population-based cohort study
.
Prostate Cancer Prostatic Dis
2021
[Online ahead of print]
.
5.
Bousset
L
,
Septier
A
,
Bunay
J
,
Voisin
A
,
Guiton
R
,
Damon-Soubeyrant
C
, et al
Absence of nuclear receptors LXRs impairs immune response to androgen deprivation and leads to prostate neoplasia
.
PLoS Biol
2020
;
18
:
e3000948
.
6.
Becerra-Diaz
M
,
Song
M
,
Heller
N
. 
Androgen and androgen receptors as regulators of monocyte and macrophage biology in the healthy and diseased lung
.
Front Immunol
2020
;
11
:
1698
.
7.
Liu
F
,
Wang
C
,
Huang
H
,
Yang
Y
,
Dai
L
,
Han
S
, et al
SEMA3A-mediated crosstalk between prostate cancer cells and tumor-associated macrophages promotes androgen deprivation therapy resistance
.
Cell Mol Immunol
2021
;
18
:
752
4
.
8.
Hagberg
CE
,
Falkevall
A
,
Wang
X
,
Larsson
E
,
Huusko
J
,
Nilsson
I
, et al
Vascular endothelial growth factor B controls endothelial fatty acid uptake
.
Nature
2010
;
464
:
917
21
.
9.
Beltraminelli
T
,
De Palma
M
. 
Biology and therapeutic targeting of tumor-associated macrophages
.
J Pathol
2020
;
250
:
573
92
.
10.
Wu
K
,
Lin
K
,
Li
X
,
Yuan
X
,
Xu
P
,
Ni
P
, et al
Redefining tumor-associated macrophage subpopulations and functions in the tumor microenvironment
.
Front Immunol
2020
;
11
:
1731
.