Received: 6 June 2020 Revised: 7 September 2020 Accepted: 21 September 2020 DOI: 10.1111/exd.14203
Activated melanoma vessels: A sticky point for successful immunotherapy Carsten Weishaupt1
| Tobias Goerge1 | Karin Loser1,2
1 Department of Dermatology, University Hospital of Muenster, Muenster, Germany
Institute of Immunology, University of Oldenburg, Oldenburg, Germany
Metastatic melanoma is a devastating disease with a marginal—albeit increasing—
Correspondence Carsten Weishaupt, Department of Dermatology, University Hospital Muenster, Von-Esmarch-Str. 58, D-48149 Muenster, Germany. Email: [email protected]
sion of numerous neo-antigens and thus is associated with the potential to induce
Funding information Arbeitsgemeinschaft Dermatologische Forschung/Deutsche Dermatologische Gesellschaft, Grant/Award Number: Forschungsstipendium; Deutsche Forschungsgemeinschaft, Grant/Award Number: 817/5-1 , 817/7-1 , SFB 1009 project B07 and SFB-TR 128 project A10; Interdisciplinary Center for Clinical Research, Grant/Award Number: Lo2/004/16
to evade from antitumoral immune responses have been characterized and must be
hope for cure. Melanoma has a high mutation rate which correlates to the expresand strengthen effective antitumoral immunity. However, the incomplete and potentially insufficient response to established immunotherapies (response rates usually do not markedly exceed 60%) already points to the need of further studies to improve treatment strategies. Multiple tumor escape mechanisms that allow melanoma overcome to achieve a better clinical efficacy of immunotherapies. Recently, promising progress has been made in targeting tumor vasculature to control and increase the infiltration of tumors with effector lymphocytes. It has been hypothesized that amplified lymphocytic infiltrates in melanoma metastases result in a switch of the tumor microenvironment from a non-inflammatory to an inflammatory state. In this view point essay, we discuss the requirements for successful homing of lymphocytes to melanoma tissue and we present a mouse melanoma xenograft model that allows the investigation of human tumor vessels in vivo. Furthermore, current clinical studies dealing with the activation of melanoma vasculature for enhanced effectiveness of immunotherapy protocols are presented and open questions for routine clinical application are addressed. KEYWORDS
adhesion molecules, animal model, drug carriers, lymphocyte homing receptors, xenografts
1 | TH E N E E D TO OV E RCO M E T U M O R E S C A PE I N M E TA S TATI C M E L A N O M A
They have promising long-term outcomes and response rates (40%-63%). However, it needs to be considered that a significant number of melanoma patients will still develop primary resistance or
Is metastatic melanoma curable?—This question has recently been asked more extensively than ever by patients and physicians.
will show progress in the course of treatment (acquired resistance).
A major cause of treatment resistance to immunotherapy is
treatment targets such as immune checkpoint blockade (ICB) with
characteristics of the tumor tissue itself that allow the tumor to es-
PD-1 and CTLA-4 antibodies have become a routine treatment.
cape from immune responses. Therefore, a fundamental need in
This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made. © 2020 The Authors. Experimental Dermatology published by John Wiley & Sons Ltd Experimental Dermatology. 2020;00:1–9.
WEISHAUPT et al.
treatment of metastatic melanoma is to better understand tumor escape mechanisms and to identify targets in order to
Early studies by Griffioen et al had shown that adhesion molecule expression in tumor angiogenesis is reduced and corresponds to a down-regulated inflammatory response.[25,26] Subsequently, it
1. increase the treatment response rate
was found that adhesion molecules relevant for lymphocyte hom-
2. reduce treatment toxicity
ing (PECAM-1, E-selectin, ICAM-1, ICAM-2, VCAM-1 and CD34)
3. increase the duration of treatment response
were sparsely expressed on melanoma vessels.[28-30] As a cause for the downregulation of adhesion molecules, angiogenic factors such
Many tumor escape mechanisms have been identified, but few
as tumor-derived VEGF, FGF, TGF-β or NO were determined.[31-33]
have been targeted effectively enough for improving existing immu-
As we could show in melanoma metastases of different origin (lung,
skin, lymph node, liver), the sparse expression of adhesion molecules correlated with low lymphocytic infiltrates. Notably, lymphocytes
2 | M E L A N O M A V E S S E L S A S TA RG E T S FO R I M M U N OTH E R A PY
accumulated in the tumor-surrounding tissue with regular expression of adhesion molecules on the vasculature. This observation triggered the hypothesis that induction of adhesion molecules on the endothelial cells of the melanoma vasculature might induce a
As an essential logistic system for nutrition and oxygen supply of tu-
sufficient lymphocytic infiltrate for more effective immune target-
mors, the characteristics of tumor vessels have been appointed as a
ing treatment protocols.
tumor escape mechanism.
They have been in the focus of research
since the early 1970s, when Judah Folkman had proposed angiogenesis as a target for tumor treatment. In tumors, the hierarchical vessel structure and blood flow are distorted.[7,8] Tumor vessels are irregularly distributed, disorganized and tortuous, and due to the interstitial pressure that is built up by the tumor mass, they are dilated and leaky. Melanoma endothelial cells have characteristics that are
3 | A M O U S E M O D E L TO S T U DY AC TI VATI O N O F H U M A N M E L A N O M A VA S C U L AT U R E 3.1 | Can human vessels be studied in vivo?
considered to be abnormal including their morphology and genetics. These tumor growth supporting characteristics have been recently
Many studies had investigated the relevance of homing marker ex-
summarized by Annan et al in detail. Drug resistance, for example,
pression in melanoma tissue. Nooijen et al reported a moderate up-
is promoted by upregulation of the multi-drug resistance receptor 1
regulation of E-selectin expression on human melanoma vasculature
and upregulation of p-glycoprotein within tumor endothelial cells.
after isolated limb perfusion with TNF and melphalan. However,
This is induced through Act signalling by VEGF.
In addition, au-
they did not observe any significant changes in ICAM-1, VCAM-1
tocrine VEGF signalling results in sustained vascular integrity and
or PECAM expression on tumor vasculature inside the tumor tis-
viability of tumor cells. During metastasis, tumor endothelial cells
sue, and moreover, they could not detect any influx of neutrophils.
prevent tumor cell anoikis by binding to tumor cells while they travel
However, in this experimental setup endothelial modulators were
to distant organs through blood and tissue.
delivered to the melanoma vessels through blood circulation. As the
On the other hand, tumor endothelial cells serve as a first anchor
authors discuss, the characteristics of tumor vessels might hamper
for immune cells to adhere and extravasate into the tumor tissue, a
a sufficient effect on the endothelium of tumor vasculature as they
process denominated as “homing”. The homing process is regu-
found a clear effect on the tumor-surrounding vessels. In addition,
lated through a tissue-specific pattern of adhesion molecules and
the study lacks information on treatment relevant effector lympho-
chemokines.[14-16] Lymphocyte homing into tumor tissue, however,
cyte infiltration inside the tumor tissue. Thus, the study left some
is associated with an effective immune response and is a positive
questions open regarding the effectiveness of endothelial modula-
predictive marker.[17-19] Furthermore, the efficacy of immunother-
tion of tumor vasculature.
apy has been correlated to the number of tumor-infiltrating lympho-
A far more promising result was presented by Calcinotto et al.
cytes. Therefore, the endothelial cells within tumor vasculature
They had studied NGR-TNF, which is TNF-α fused to a tumor-hom-
have been pinpointed as a target for investigations and therapeutic
ing peptide that recognizes an aminopeptidase N (CD13) isoform.
It is selectively expressed by endothelial cells in tumors. The fu-
Initial studies in the 1990s aiming at defining adhesion molecule
sion protein was able to induce ICAM-1, ICAM-2 and VCAM-1 on
expression on tumor vasculature were undertaken to develop mel-
tumor vasculature in a B16 melanoma mouse model. This led
anoma vaccination protocols or antigen unspecific immunotherapy
to the release of pro-inflammatory cytokines and chemokines and
concepts (interferon-α, interleukin-2, isolated limb perfusion with
the infiltration of tumor-specific effector CD8+ T cells. Indeed, this
Recent antigen non-specific approaches like CTLA-4
model allows studying immune responses to melanoma in an immu-
and PD-1 inhibition still require homing prerequisites, like adhesion
nocompetent mouse and it also allows to investigate immunothera-
molecule expression on tumor vasculature and chemokine gradients
peutic approaches. However, at least anti-angiogenic treatments
inside tumor tissue for effective immune infiltration.
have been less effective in humans than predicted on the basis of
WEISHAUPT et al.
preclinical tests in mice. Thus, the investigation of human vessels in
with relevant supply of melanoma grafts by human vessels. During
a melanoma xenograft model appears to be preferable for the inves-
the determined time frame of 21 days, cell homing studies indepen-
tigation of endothelial modification in vivo while other models may
dent on the type of leucocyte appear to be feasible. Certainly, the
be preferable in other demands.
limitations of the model have to be taken into account. The whole set
Such a model should be able to prove that
up is elaborate and for comparability the donated blood and tumor tissues need to be sufficient. Thus, dependent on the availability
1. Human melanoma vasculature can be activated to express adhesion molecules 2. Induction of adhesion molecules results in enhanced recruitment of lymphocytes into melanoma tissue Few studies had investigated the usefulness of human vasculature in human tumor grafts on mice. Summarized, they found that the supply of grafted human tumor tissue in colon carcinoma and mesothelioma was provided by mouse vessels of the host
of tissues, experiments may be prolonged. Effects of host-derived cytokines and angiogenic factors on the graft including the innate immune system and complement system are not known so far. Thus, effective controls are needed.
4 | R EQ U I R E M E NT S FO R E FFEC TI V E LY M PH O C Y TE H O M I N G TO M E L A N O M A M E TA S TA S E S
that started spreading into the tumor tissue after implantation of the graft. Similar to the study on colon carcinoma grafts, we trans-
Employing the in vivo model, three requirements for homing to
planted tissue from human melanoma metastases onto immunode-
human melanoma tissue were found (Figure 1):
ficient NOD-scid-IL2Rgammanull (NSG) mice. With this model, we were able to better characterize the function of human vessels inside melanoma xenografts. We utilized a FITC labelled lectin specific for human vasculature that exclusively stained human vessels
4.1 | Activation of vascular endothelium results in enhanced lymphocyte homing to melanoma tissue
when injected into mouse circulation. As we found lectin stained human vessels inside the melanoma grafts, we were able to prove
Comparable to the finding of Calcinotto and co-workers in the B16
that human vessels inside xenografts connect to the mouse circula-
mouse model, we found that intratumoral injection of endothelial ac-
tion at day 7-14 after transplantation and can be studied until day 21
tivators like TNF resulted in an upregulation of adhesion molecules
before mouse vessels take over and outnumber human vessels. This
such as ICAM-1 and E-selectin. More importantly, we could show
observation was the first evidence that human melanoma vessels
that induction of these adhesion molecules on human melanoma
can be investigated in vivo when considering the limited time frame
vasculature resulted in enhanced infiltration of human lymphocytes
F I G U R E 1 The prerequisites of lymphocyte homing to melanoma tissue are shown. Relevant homing receptors are indicated
WEISHAUPT et al.
from the same patient which were injected intravenously into the
cells counts in the tumor.[47,48] Others have found that also CCL3,
mouse. These results confirmed that activation of the melanoma
CCL4 and CCL5 contribute to lymphocyte invasion into melanoma
vasculature may be helpful to stimulate immune responses against
tissue. In our study, we could add CCL17 (TARC), a ligand of
the tumor and within the tumor.
CCR4, as a chemokine that effectively triggers lymphocyte hom-
However, the results also showed that two additional condi-
ing to melanoma tissue when a gradient is established through in-
tions for effective leucocyte homing to melanoma tissue have to be
tralesional injection. Of note, a recent study demonstrated that
macrophage-derived CXCR3 ligands CCL9/CCL10 are required for antitumor immune responses following ICB
4.2 | Activated lymphocytes are needed for effective homing Grafted T-lymphocytes had to be taken from the same patient and had to be activated by incubation with tumor lysate from the same patient to gain homing to melanoma metastases. This suggests that imprinting of specialized homing molecules onto effec-
clinical relevance of homing markers for established immunotherapy protocols.
5 | O PE N Q U E S TI O N S A N D E X PE R I M E NTA L A PPROAC H E S TO TA K E AC TI VATI O N O F T U M O R V E S S E L S TO C LI N I C A L A PPLI C ATI O N
tor T-lymphocytes must have taken place before cells were obtained from the patient. This was in line with others who had postulated
Since preclinical observations have suggested the activation of
that T-lymphocytes need to be activated for effective homing into
tumor vessels as an additional treatment to immunotherapies, some
tumor tissue.[40-43] An earlier study had shown similar homing re-
remaining questions have to be answered to implement this ap-
ceptor expression on peripheral blood CD8+ T cells in melanoma
proach in clinical melanoma treatment.
patients and healthy donors in a small cohort (n = 11) suggesting that tumor-infiltrating lymphocytes might not present a skin-specific homing profile. Therefore, the role of homing receptors on effector lymphocytes and mechanisms to modify these has to be reevaluated. To address this, studies on lymphocyte homing patterns (eg expression of LFA-1, MAC-1, PSGL-1 and VLA-4) in blood and mela-
5.1 | Can we specifically target endothelial modulators to tumor vasculature to improve efficacy of endothelial activation and for better tolerability?
noma tissue-derived cells from patients responding or progressing under PD-1 and/or CTLA-4 antibody treatment will provide useful
Treatment with TNF has side effects. While intralesional injection or
even isolated limb perfusion of TNF can be tolerated well, this is not
Furthermore, some immunotherapeutic approaches allow ge-
the case for systemic application. However, isolated limb perfu-
netic modification of T-lymphocytes, such as CAR-T cells, that
sion did not result in an effective stimulation of melanoma vessel
need to be prepared to home to tumor tissue. Chemokine re-
endothelium. Thus, a carrier that delivers endothelial modulators
ceptor modification on tumor-specific lymphocytes may also help
specifically to tumor vasculature is desirable. Calcinotto et al have
to target effector cells more efficiently to the tumor. For instance,
shown that NGR conjugated to human TNF is able to specifically
Idorn et al had recently shown that lentiviral transduction of
enhance adhesion molecule expression in a B16 mouse melanoma
T-lymphocytes with the chemokine receptor CXCR2 increased hom-
model. NGR-humanTNF (NGR-hTNF) has already been investi-
ing of CD8 + lymphocytes to tumor tissue.
gated in phase I-III studies in various tumors.[52-55] The drug has been well tolerated and demonstrated clinical activity. However, most of
4.3 | Chemokine gradients are needed for effective homing
the studies combined NGR-hTNF treatment with chemotherapy since the drug enhanced penetration of the chemotherapy into the tumor tissue for better efficacy. Only a phase I study by Parmiani et al investigated the effect of NGR-hTNF in advanced melanoma.
However, enhanced expression of adhesion molecules might not
Here, NGR-hTNF treatment was combined with a peptide-based
be enough for efficient lymphocyte homing. A tissue-specific
vaccination in 8 patients. Analysis of the immune infiltrate before
chemokine gradient is also a requirement. In the humanized mouse
and after treatment did not reveal an increased effector lymphocyte
model, the number of infiltrating T-lymphocytes did not increase
infiltrate, but increased numbers of macrophages inside the tumor.
without additional establishment of a chemokine gradient within
A clear tumor response was not detected while a prolonged survival
the tumor tissue. Chemokine receptors such as CXCR3 and CCR5
was discussed. However, neither adhesion nor chemokine receptors
have been shown to be important for effective tumor infiltration
analysis was performed on the tumor vasculature or lymphocytes.
with cytotoxic T-lymphocytes.[30,46] Along this line, the expression
Thus, a clinical trial to analyse the clinical effectiveness of ICB plus
of their ligands CXCL9 and CXCL10 in melanoma tissue correlates
NGR-hTNF treatment might be necessary to answer this ques-
not only with enhanced CTL infiltrates but also with increased NK
tion. It should include a translational part that investigates homing
WEISHAUPT et al.
TA B L E 1 Therapeutic targets of tumor vasculature in melanoma and ongoing clinical trials Target
Neoadjuvant intratumoral treatment followed by surgery versus surgery alone
Melanoma with injectable lesion, no visceral metastases
T-vec + intratumoral injection of CD1c (BDCA-1)+ myDC
bevacizumab + ipilimumab ipilimumab ± bevacizumab
Mucosal melanoma, metastasized or locally advanced
bevacizumab + atezolizumab
Bevacizumab + atezolizumab
Melanoma brain metastasis
bevacizumab + pembrolizumab
Melanoma brain metastasis
bevacizumab + pembrolizumab ± cobimetinib
+ paclitaxel albumin-stabilized nanoparticle formulation
TRK-950 + bevacizumab or other drugs
Bevacizumab vs dacarbacin
Melanoma IIB,IIC, IV
Bevacizumab + Carboplatin/ paclitaxel
receptors before and after treatment on melanoma vasculature and
modifying the immune response to melanoma. However, the effect
needs to be confirmed in a controlled clinical trial preferentially in
Another entry to stimulate melanoma vasculature is the L19 an-
patients treated with ICB.
tibody which recognizes tumor-specific fibronectin. For clinical
In addition to stimulation of vascular adhesion molecules, at-
application, it has been fused to interleukin-2 and TNF.[58,59] A phase
tempts to prevent downregulation of adhesion molecules on mela-
II study in melanoma has shown that the intralesional combination
noma vessels during angiogenesis by VEGF-α have been undertaken
to normalize tumor vessels for better lymphocytic infiltrates.
and that it was well tolerated. The results of a neoadjuvant phase
Here, immunization against VEGFR-2 or the adoptive transfer of
III study (NCT02938299) are pending. L19-TNF has also been com-
autologous T cells genetically engineered to express a chimeric an-
bined with ICB. After an improved response rate of ipilimumab and
tigen receptor targeted against VEGFR-2 has been employed and
L19-TNF was demonstrated in two syngeneic murine tumor mod-
has shown prolonged tumor-free survival in a mouse model.[65-67]
of these immunocytokines resulted in a response rate of 55%
els (F9, CT23),
a very recent study in a BALB/c derived immuno-
Furthermore, treatment with VEGF-α antibodies has raised hope to
competent murine model of sarcoma (WEHI-164) revealed that the
increase effectiveness of established immunotherapies by increas-
combination of L19-TNF and PD-1 inhibition was significantly more
ing lymphocytic infiltrates in melanoma tissue.[68,69] A clinical phase
effective than PD-1 inhibition alone.
These results, if confirmed
I has combined the CTLA-4 antibody ipilimumab and the VEGF-α
in clinical trials, will have major implications for the standard care of
antibody bevacizumab for treatment of metastatic melanoma. A
human cancers, including melanomas.
clinical response was documented demonstrating a disease control
An entirely different approach to activate tumor vasculature was chosen by Ito et al.
rate of 67,4% with an enhanced immunological response mediated
They found that adhesion receptors can be
through IL1α, TNFα and CXCL10, together with VEGF neutralization
induced on tumor vasculature by radiofrequency ablation in human
and a tolerable toxicity. Thus, further clinical studies including the
melanomas grafted on mice, resulting in enhanced lymphocyte infil-
combination of PD-1 or PD-L1 antibodies with VEGF-α antibodies
trates. These data point to a clinically easily accessible technique for
are warranted and have already shown clinical effectivity in an early
WEISHAUPT et al.
study for renal cell carcinoma. A line-up with therapeutic targets
L19-IL2 and L19-TNF. In this study, a response of non-injected me-
and ongoing clinical trials can be reviewed in Table 1.
tastases was observed in 7/13 cases.
5.2 | Who needs adjuvant stimulation of tumor vessels?
6 | W I LL M E TA S TATI C M E L A N O M A B E CU R A B LE I N 10 Y E A R S ?
This is an important question in order to determine what patient
Now that immunotherapy is established for the treatment of mela-
population will at all profit from additional activation of tumor ves-
noma it is time to sharpen this tool for more effective and individual
sels. Analysis of molecular profiles and immune cell composition
melanoma treatment. To do so, many details of the immune re-
have suggested a differentiation between inflamed tumors (hot tu-
sponses to melanoma and the immune escape mechanisms still have
mors) and non-inflamed tumors (cold tumors). More recently 6
to be explored, understood and the results need to be implemented
tumor profiles have been suggested, described as “wound healing,”
into immunotherapy protocols. Activation of tumor vessels for en-
“IFN-γ-dominant,” “inflammatory,” “lymphocyte depleted,” “immu-
hanced lymphocyte infiltration is one of many targets. In the long
nologically quiet,” and “TGF-β dominant”. “Wound healing,” “IFN-γ-
run, multiple adjuvant treatments may be necessary to boost the al-
dominant,” “inflammatory,” and “lymphocyte depleted” are the most
ready existing immune checkpoint therapies. These adjuvant treat-
frequent categories found in melanoma. Since the “inflammatory”
ments will be applied dependent on the category of the tumor. Thus,
subset has been associated to the best prognostic value, the “lym-
the identification of the tumor category will be a prerequisite for
phocyte depleted” tumors may be targets for additional activation
successful personalized tumor medicine. Especially for non-inflamed
of tumor vasculature. Yet, it has to be tested which tumor category
melanomas stimulation of a pro-inflammatory tumor microenviron-
will be the most suitable target for additional activation of tumor
ment might be essential for successful immunotherapy. Based on
vasculature. It is unlikely that melanoma of the various categories
the recent findings on modulation of the tumor vasculature, this ap-
can be established in a mouse model. Thus, this question will have
proach is highly promising and has progressed to investigation within
to be answered in clinical studies that compare the tumor response
clinical studies (Table 1). The sticking point will be the delivery of
to immunotherapy plus vascular stimulation for the different tumor
efficient endothelial modulators to the tumor vessels. Here effective
carriers of endothelial modulators need to be found. NGR-TNF or L19-TNF is promising drugs that hopefully will take us closer to cure
5.3 | Is local activation of the tumor vasculature by intralesional treatment enough to trigger a systemic immune response?
melanoma more often within 10 years. AC K N OW L E D G M E N T S We thank Meike Steinert for expert technical support. Financial support by the “ADF/DDG Forschungsstipendium” to CW, Deutsche
The “abscopal effect” is a phenomenon that describes a systemic
Forschungsgemeinschaft (DFG; SFB-TR 128 project A10 to KL,
immune response with regression of non-treated metastases, when
SFB 1009 project B07 to KL, projects 817/5-1 and 817/7-1 to KL)
local radiation therapy is undertaken. Radiation therapy has
and the Interdisciplinary Center for Clinical Research (IZKF, project
been shown to induce abscopal effects in metastatic melanoma,
Lo2/004/16 to KL) is gratefully acknowledged. Open access funding
but also other lesion directed treatment approaches have demon-
enabled and organized by Projekt DEAL. Open access funding ena-
strated similar effects. Already in the 70ies Rosenberg et al had ob-
bled and organized by ProjektDEAL.
served that intralesional treatment of melanoma metastases with Mycobacterium bovis Bacillus-Calmette-Guérin resulted in shrink-
C O N FL I C T O F I N T E R E S T
ing of untreated metastases. Another pro-inflammatory approach
is intralesional injection of Talimogen laherparepvec, an oncolytic virus that specifically targets tumor cells, converts tumor cell me-
AU T H O R C O N T R I B U T I O N S
tabolism to produce the immune stimulant GM-CSF and induces cell
CW, TG and KL have written the manuscript and have read and ap-
lysis. Impressively, it has displayed an abscopal response in 15% of
proved the final manuscript.
uninjected visceral metastases. Whether abscopal responses can be achieved by vascular stimu-
DATA AVA I L A B I L I T Y S TAT E M E N T
lation, for instance in combination with PD-1 antibodies needs to be
Data sharing not applicable to this article as no data sets were gener-
answered in a clinical study that will compare intralesional treatment
ated or analysed during the current study.
with endothelial modulators with and without ICB. In addition, the tumor volume that needs to be treated intralesionally to achieve a
systemic immune response has to be investigated. First promising
results stem from a phase II study on intralesional treatment with
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How to cite this article: Weishaupt C, Goerge T, Loser K. Activated melanoma vessels: A sticky point for successful immunotherapy. Exp Dermatol. 2020;00:1–9. https://doi. org/10.1111/exd.14203