Summary:

In this issue of Cancer Discovery, Pelly and colleagues show that inhibition of prostaglandin E2 synthesis or its activity on EP2 and EP4 receptors synergizes with anti–PD-1 immunotherapy and triggers a potent intratumoral IFNγ response in mouse models and in fresh surgical human tumor explants. This therapeutic strategy is in line with other interventions that aim at fostering immunotherapy by means of quenching protumor inflammation.

See related article by Pelly et al., p. 2602.

Inflammation is a response of vascularized tissues of the organism to damaging agents. Inflammation intends to drive into the tissue means to eliminate the damaging agent and repair the organ. In cancer and carcinogenesis, innate inflammation driven by myeloid leukocytes is often protumoral and is considered a hallmark of cancer (1). Conversely, cellular immunity mainly mediated by IFNγ-secreting T and natural killer (NK) lymphocytes is able to control tumor progression, and the upregulation of these cytolytic functions is the target of clinically successful immunotherapies with checkpoint inhibitors. These two types of inflammation collide in attempts to treat cancer, and it makes sense to quench one of them while fueling the other.

Inflammation is orchestrated by so-called soluble inflammatory mediators that are synthesized or released in the compromised tissue to change the vasculature, so it permits exudate extravasation and makes it prone to intake immunosuppressive myeloid cells such as polymorphonuclear leukocytes and macrophages. This type of acute inflammation is ignited and controlled by small molecules, including lipid mediators such as prostaglandins and leukotrienes, as well as by chemokine and cytokine proteins.

Prostaglandins have been a very fruitful therapeutic target to deal with inflammation. A broad pharmacologic family of NSAIDs exerts its effects at least partly because of blocking COX enzymes that synthesize prostaglandin H2 from arachidonic acid (Fig. 1A). Prostaglandin E2 (PGE2), synthesized by PGE2 synthase, has been found to be immunosuppressive in mouse models. Indeed, the group of George Coukos had pioneered the concept in ovarian cancer models that COX inhibition with acetylsalicylate was able to promote T-cell infiltration acting on endothelial cells in cancer tissue and to synergize with other immunotherapies (2, 3). The groups of Santiago Zelenay and Caetano Reis e Sousa have been able to demonstrate an interesting set of phenomena dependent on the expression of the two COX isoforms (COX1 and COX2) in cancer cells. In their transplantable melanoma systems, elimination of these enzymes in tumor cells increased the content of NK cells in the tumor microenvironment (4). Because of this, NK cells attracted BAFT3-dependent type I dendritic cells, able to mediate cross-priming of tumor antigens to cognate CD8+ T lymphocytes (5). In this issue of Cancer Discovery, the group of Santiago Zelenay goes one step forward, showing that pharmacologic inhibitors of COX2 could be combined with checkpoint inhibitors to attain better immunotherapeutic responses in transplantable mouse tumor models (6). COX2-selective inhibitors have been developed by the pharmaceutical industry to avoid the gastric toxicity and antiplatelet aggregation effects of COX1 inhibition. The biochemical pathway of PGE2 synthesis and its paracrine action on EP2 and EP4 receptors can be pharmacologically interfered with at the level of COX-mediated synthesis or by competitive blockers of the PGE2 receptors (EP2 and EP4) coupled to adenylate cyclases mediating cyclic adenosine monophosphate (cAMP) synthesis (Fig. 1A). Increased intracellular cAMP mediates multiple processes, but in T cells, recent evidence shows that it can be critical to activate HPK1, which is an enzyme involved in T-cell exhaustion induction (7) and suppression of antitumoral adaptive immune responses. As a result of interference with PGE2 synthesis or function, mouse tumors acquire expression of genes that denote IFNγ activation in a fashion that correlates with antitumor therapeutic responses. Very elegantly, this is also tested in short-term cultures of freshly explanted surgical specimens of human tumors, where these changes of gene expression are recapitulated in conjunction with the addition of PD-1/PD-L1 inhibitors. Of note, retrospective analyses of the use of NSAIDs in patients with melanoma receiving PD-1/PD-L1 blocking agents are suggestive of some beneficial effects that need to be prospectively confirmed (8).

Figure 1.

Interference with soluble inflammatory mediators to synergize with checkpoint inhibitor–based cancer immunotherapy. A, Schematic route of PGE2 synthesis by a pathway catalyzed by phospholipase A (PLA), COX1 or COX2, and PGE2 synthase. PGE2 in the tumor milieu acts paracrinally on its receptors EP2 and EP4, increasing intracellular cAMP via adenylate cyclase activation. This second messenger activates HPK1, among other elements involved in T- and NK-cell dysfunction. The route is druggable with COX2 and/or COX1 inhibitors, as well as with EP2/EP4 inhibitors already available or in development. Pelly and colleagues (6) demonstrate that this kind of pharmacologic intervention synergizes with PD-1 blockade in mouse models and in fresh surgical tumor explants set in culture. B, Summary of soluble inflammatory mediators that can be drugged with existing agents and whose inhibition has been shown to synergize with checkpoint inhibitors at the preclinical and in some cases at the clinical level. Firefighters in the scheme represent these pharmacologic interventions that quench the wrong type of inflammation in tumors to allow for more effective immune checkpoint blockade as a result of reshaping the tumor tissue microenvironment. This figure was created with BioRender.com with elements from Freepick.

Figure 1.

Interference with soluble inflammatory mediators to synergize with checkpoint inhibitor–based cancer immunotherapy. A, Schematic route of PGE2 synthesis by a pathway catalyzed by phospholipase A (PLA), COX1 or COX2, and PGE2 synthase. PGE2 in the tumor milieu acts paracrinally on its receptors EP2 and EP4, increasing intracellular cAMP via adenylate cyclase activation. This second messenger activates HPK1, among other elements involved in T- and NK-cell dysfunction. The route is druggable with COX2 and/or COX1 inhibitors, as well as with EP2/EP4 inhibitors already available or in development. Pelly and colleagues (6) demonstrate that this kind of pharmacologic intervention synergizes with PD-1 blockade in mouse models and in fresh surgical tumor explants set in culture. B, Summary of soluble inflammatory mediators that can be drugged with existing agents and whose inhibition has been shown to synergize with checkpoint inhibitors at the preclinical and in some cases at the clinical level. Firefighters in the scheme represent these pharmacologic interventions that quench the wrong type of inflammation in tumors to allow for more effective immune checkpoint blockade as a result of reshaping the tumor tissue microenvironment. This figure was created with BioRender.com with elements from Freepick.

Close modal

Neutralization of PGE2 functions joins the list of agents that act via inhibiting soluble substances that elicit the wrong type of protumor inflammation in cancer. Among other small molecules, adenosine, which can be acted upon its synthesis via the CD39 and CD73 ectoenzymes or the ADAR receptors, is perhaps the most studied mediator, and clinical trials with blocking agents are undergoing (9).

However, the most harmful soluble mediators for cancer immunotherapy with checkpoint inhibitors are probably proteins in the form of cytokines and chemokines. Cumulative evidence is showing that TGFβ (10), IL1β (11), TNFα (12), IL6/IL6R (13), LIF (14), and GDF15 (15) promote the inflammation type that is damaging for adaptive cytotoxic T-cell immunity. Importantly, neutralizing agents developed in the field of rheumatology are available for some of these cytokines, and clinical trials are ongoing to repurpose such agents in combination with checkpoint inhibitors.

Moreover, the leukocyte composition of the tumor microenvironment is largely dictated by chemokines and their receptors. Evidence on the negative role of CXCR1/2 agonists such as CXCL8 (IL8; ref. 16) or CXCL1 as produced by human solid and hematologic malignancies is mounting (17) and being pharmacologically targeted in combination with checkpoint inhibitors (NCT03400332). CXCR4 and its ligands CXCL12 or CXCL7 also mediate the shaping of protumor myeloid infiltrates, and its interference in conjunction with chemotherapy and pembrolizumab has shown activity in metastatic pancreatic cancer (18). Because of the role of CCR2 and CCL2 in recruiting macrophages (19) and the role of CCR4 at recruiting regulatory T cells (20), these chemokine pathways are also attractive to be inhibited in immunotherapy combinations.

A common theme emerges in which, for immunotherapy based on checkpoint inhibitors, a drastic reprogramming of the inflammatory status of the tumor is useful. The good news is that we already have a broad pharmacologic armamentarium that can be repurposed, as in the case of interference with the PGE2 pathway. Figure 1B summarizes a number of targets among inflammatory mediators that are being antagonized for immunotherapy purposes. Paradoxically, cancer immunotherapists are likely to become arsonists and firefighters at the same time.

I. Melero reports grants and personal fees from BMS, Roche, AstraZeneca, Bioncotech, Alligator, Genmab, Pharmamar; personal fees from F-Star; and personal fees from F-Star, Numab, and Gossamer outside the submitted work. P. Berraondo reports grants from Sanofi, Ferring, Bavarian Nordic, Hookipa, Moderna, BMS, MSD, Novartis, and Boehringer Ingelheim, and personal fees from AstraZeneca outside the submitted work. No disclosures were reported by the other authors.

1.
Hanahan
D
,
Weinberg
RA
. 
Hallmarks of cancer: the next generation
.
Cell
2011
;
144
:
646
74
.
2.
Motz
GT
,
Santoro
SP
,
Wang
LP
,
Garrabrant
T
,
Lastra
RR
,
Hagemann
IS
, et al
Tumor endothelium FasL establishes a selective immune barrier promoting tolerance in tumors
.
Nat Med
2014
;
20
:
607
15
.
3.
Chiang
CL
,
Kandalaft
LE
,
Tanyi
J
,
Hagemann
AR
,
Motz
GT
,
Svoronos
N
, et al
A dendritic cell vaccine pulsed with autologous hypochlorous acid-oxidized ovarian cancer lysate primes effective broad antitumor immunity: from bench to bedside
.
Clin Cancer Res
2013
;
19
:
4801
15
.
4.
Zelenay
S
,
van der Veen
AG
,
Bottcher
JP
,
Snelgrove
KJ
,
Rogers
N
,
Acton
SE
, et al
Cyclooxygenase-dependent tumor growth through evasion of immunity
.
Cell
2015
;
162
:
1257
70
.
5.
Sanchez-Paulete
AR
,
Teijeira
A
,
Cueto
FJ
,
Garasa
S
,
Perez-Gracia
JL
,
Sanchez-Arraez
A
, et al
Antigen cross-presentation and T-cell cross-priming in cancer immunology and immunotherapy
.
Ann Oncol
2017
;
28
:
xii44
55
.
6.
Pelly
VS
,
Moeini
A
,
Roelofsen
LM
,
Bonavita
E
,
Bell
CR
,
Hutton
C
, et al
Anti-inflammatory drugs remodel the tumor immune environment to enhance immune checkpoint blockade efficacy
.
Cancer Discov
2021
;11:2602–19.
7.
Si
J
,
Shi
X
,
Sun
S
,
Zou
B
,
Li
Y
,
An
D
, et al
Hematopoietic progenitor kinase1 (HPK1) mediates T cell dysfunction and is a druggable target for T cell-based immunotherapies
.
Cancer Cell
2020
;
38
:
551
66
.
8.
Wang
SJ
,
Khullar
K
,
Kim
S
,
Yegya-Raman
N
,
Malhotra
J
,
Groisberg
R
, et al
Effect of cyclooxygenase inhibitor use during checkpoint blockade immunotherapy in patients with metastatic melanoma and non-small cell lung cancer
.
J Immunother Cancer
2020
;
8
:
e000889
.
9.
Vijayan
D
,
Young
A
,
Teng
MWL
,
Smyth
MJ
. 
Targeting immunosuppressive adenosine in cancer
.
Nat Rev Cancer
2017
;
17
:
709
24
.
10.
Batlle
E
,
Massague
J
. 
Transforming growth factor-beta signaling in immunity and cancer
.
Immunity
2019
;
50
:
924
40
.
11.
Wong
CC
,
Baum
J
,
Silvestro
A
,
Beste
MT
,
Bharani-Dharan
B
,
Xu
S
, et al
Inhibition of IL1beta by canakinumab may be effective against diverse molecular subtypes of lung cancer: an exploratory analysis of the CANTOS trial
.
Cancer Res
2020
;
80
:
5597
605
.
12.
Perez-Ruiz
E
,
Minute
L
,
Otano
I
,
Alvarez
M
,
Ochoa
MC
,
Belsue
V
, et al
Prophylactic TNF blockade uncouples efficacy and toxicity in dual CTLA-4 and PD-1 immunotherapy
.
Nature
2019
;
569
:
428
32
.
13.
Rossi
JF
,
Lu
ZY
,
Jourdan
M
,
Klein
B
. 
Interleukin-6 as a therapeutic target
.
Clin Cancer Res
2015
;
21
:
1248
57
.
14.
Pascual-Garcia
M
,
Bonfill-Teixidor
E
,
Planas-Rigol
E
,
Rubio-Perez
C
,
Iurlaro
R
,
Arias
A
, et al
LIF regulates CXCL9 in tumor-associated macrophages and prevents CD8(+) T cell tumor-infiltration impairing anti-PD1 therapy
.
Nat Commun
2019
;
10
:
2416
.
15.
Wischhusen
J
,
Melero
I
,
Fridman
WH
. 
Growth/differentiation factor-15 (GDF-15): from biomarker to novel targetable immune checkpoint
.
Front Immunol
2020
;
11
:
951
.
16.
Schalper
KA
,
Carleton
M
,
Zhou
M
,
Chen
T
,
Feng
Y
,
Huang
SP
, et al
Elevated serum interleukin-8 is associated with enhanced intratumor neutrophils and reduced clinical benefit of immune-checkpoint inhibitors
.
Nat Med
2020
;
26
:
688
92
.
17.
Teijeira
A
,
Garasa
S
,
Ochoa
MC
,
Villalba
M
,
Olivera
I
,
Cirella
A
, et al
IL8, neutrophils, and NETs in a collusion against cancer immunity and immunotherapy
.
Clin Cancer Res
2021
;
27
:
2383
93
.
18.
Bockorny
B
,
Semenisty
V
,
Macarulla
T
,
Borazanci
E
,
Wolpin
BM
,
Stemmer
SM
, et al
BL-8040, a CXCR4 antagonist, in combination with pembrolizumab and chemotherapy for pancreatic cancer: the COMBAT trial
.
Nat Med
2020
;
26
:
878
85
.
19.
Lim
SY
,
Yuzhalin
AE
,
Gordon-Weeks
AN
,
Muschel
RJ
. 
Targeting the CCL2-CCR2 signaling axis in cancer metastasis
.
Oncotarget
2016
;
7
:
28697
710
.
20.
Marshall
LA
,
Marubayashi
S
,
Jorapur
A
,
Jacobson
S
,
Zibinsky
M
,
Robles
O
, et al
Tumors establish resistance to immunotherapy by regulating Treg recruitment via CCR4
.
J Immunother Cancer
2020
;
8
:
e000764
.