UNIVERSITATIS OULUENSIS MEDICA ACTA D D 1528 ACTA Tiia Honkanen OULU 2019 D 1528 Tiia Honkanen MORE EFFICIENT USE OF HER TARGETING AGENTS IN CANCER THERAPY UNIVERSITY OF OULU GRADUATE SCHOOL; UNIVERSITY OF OULU, FACULTY OF MEDICINE; MEDICAL RESEARCH CENTER OULU; OULU UNIVERSITY HOSPITAL
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UNIVERSITY OF OULU P .O. Box 8000 F I -90014 UNIVERSITY OF OULU FINLAND
A C T A U N I V E R S I T A T I S O U L U E N S I S
University Lecturer Tuomo Glumoff
University Lecturer Santeri Palviainen
Senior research fellow Jari Juuti
Professor Olli Vuolteenaho
University Lecturer Veli-Matti Ulvinen
Planning Director Pertti Tikkanen
Professor Jari Juga
University Lecturer Anu Soikkeli
Professor Olli Vuolteenaho
Publications Editor Kirsti Nurkkala
ISBN 978-952-42-2343-8 (Paperback)ISBN 978-952-42-2344-5 (PDF)ISSN 0355-3221 (Print)ISSN 1796-2234 (Online)
U N I V E R S I TAT I S O U L U E N S I S
MEDICA
ACTAD
D 1528
AC
TAT
iia Honkanen
OULU 2019
D 1528
Tiia Honkanen
MORE EFFICIENT USE OFHER TARGETING AGENTSIN CANCER THERAPY
UNIVERSITY OF OULU GRADUATE SCHOOL;UNIVERSITY OF OULU,FACULTY OF MEDICINE;MEDICAL RESEARCH CENTER OULU;OULU UNIVERSITY HOSPITAL
ACTA UNIVERS ITAT I S OULUENS I SD M e d i c a 1 5 2 8
TIIA HONKANEN
MORE EFFICIENT USE OF HER TARGETING AGENTS IN CANCER THERAPY
Academic dissertation to be presented with the assent ofthe Doctoral Training Committee of Health andBiosciences of the University of Oulu for public defencein Auditorium 7 of Oulu University Hospital, on 18October 2019, at 12 noon
Reviewed byDocent Minna TannerDocent Maria Sundvall
ISBN 978-952-62-2343-8 (Paperback) ISBN 978-952-62-2344-5 (PDF)
ISSN 0355-3221 (Printed)ISSN 1796-2234 (Online)
Cover DesignRaimo Ahonen
JUVENES PRINTTAMPERE 2019
OpponentProfessor Jorma Isola
Honkanen, Tiia, More efficient use of HER targeting agents in cancer therapy. University of Oulu Graduate School; University of Oulu, Faculty of Medicine; MedicalResearch Center Oulu; Oulu University HospitalActa Univ. Oul. D 1528, 2019University of Oulu, P.O. Box 8000, FI-90014 University of Oulu, Finland
Abstract
Cancer treatments have remarkably improved over the past years since targeted therapies andimmunotherapy have been introduced to the field of oncology. The benefit of these new therapiesis often limited, however, by de novo or acquired therapy resistances, which should be noticedwhen making clinical decisions.
In this current work, we studied the prognostic and predictive values of several immunologicalmarkers in metastatic HER2-positive breast cancer treated with trastuzumab, because trastuzumabis still given to patients according to the HER2 status only, without certainty of tumor response.We also determined the role of HER2 and HER3 for cancer stem cells (CSC) in ALK translocatednon-small cell lung cancer (NSCLC) cell lines since the CSCs are causing therapy resistance andcancer recurrence.
The results demonstrated that a high number of cytotoxic T cells, together with a high numberof M1-like macrophages in the center of the tumor (CT), are promising and independentprognostic factors in HER2-positive breast cancer. These markers together also can predict theprogression of the disease and the length of trastuzumab discontinuation in tumor response.Expression of HER2 and HER3 increased the stem-like properties of ALK translocated NSCLCcells, which were decreased when the expressions were downregulated. HER2-HER3-dependentCSCs also mediated the ALK therapy resistance.
In conclusion, this study suggests that patients with a favorable immunological tumor profile(high number of cytotoxic T cells and M1-like macrophages in the CT) could be treated in a less-intensive manner, that trastuzumab discontinuation could be feasible for these patients, and thattargeting of HER2 and HER3 receptors can lead to more effective killing of cancer stem-like cellsand should be further studied.
Keywords: ALK, breast cancer, cancer stem cell, ERBB, HER2, HER3, NSCLC,trastuzumab, tumor-infiltrating lymphocytes
Honkanen, Tiia, HER-proteiineja kohdentavien lääkkeiden tehokkaampi käyttösyöpähoidoissa. Oulun yliopiston tutkijakoulu; Oulun yliopisto, Lääketieteellinen tiedekunta; Medical ResearchCenter Oulu; Oulun yliopistollinen sairaalaActa Univ. Oul. D 1528, 2019Oulun yliopisto, PL 8000, 90014 Oulun yliopisto
Tiivistelmä
Syöpähoidot ovat kehittyneet huomattavasti, kun kohdennetut hoidot ja immunologiset hoidotovat tulleet perinteisten hoitojen rinnalle. Usein näiden hoitojen hyötyä kuitenkin rajoittaa joolemassa oleva lääkeresistenssi tai sen kehittyminen, mikä tulisi ottaa huomioon hoitoja suunni-teltaessa.
Tässä työssä tutkittiin immunologisia merkkiaineita, joilla voitaisiin ennustaa trastutsumabi-hoidon vastetta sekä potilaiden ennustetta levinneessä HER2-positiivisessa rintasyövässä. Tällähetkellä trastutsumabi-hoitopäätös tehdään pelkän HER2-geenimonistuman mukaan ilman var-muutta siitä, hyötyykö potilas oikeasti hoidosta. Lisäksi tutkimme HER2- ja HER3-reseptorienmerkitystä syövän kantasoluille ALK-translokoituneessa ei-pienisoluisessa keuhkosyövässä(NSCLC), sillä syövän kantasolut ovat yksi merkittävimmistä tekijöistä lääkeresistenssin kehit-tymisessä ja syövän uusiutumisessa.
Työssä havaittiin, että kasvaimen keskellä oleva suuri määrä sytotoksisia T-soluja sekä M1-tyypin makrofageja on yhteydessä potilaiden parempaan ennusteeseen ja että kyseiset merkkiai-neet ovat toisistaan riippumattomia. Merkkiaineet pystyivät ennustamaan myös taudin etenemis-tä sekä trastutsumabi-hoitokeskeytyksen pituutta. HER2- ja HER3-proteiinien tuotto lisäsi ALK-translokoituneiden NSCLC-solujen kantasolumaisia ominaisuuksia, jotka puolestaan vähenivät,kun proteiinien tuotto estettiin. Lisäksi HER2-HER3 -riippuvaiset syövän kantasolut säätelivätlääkeresistenssiä kyseisessä taudissa.
Työn tulokset viittaavat siihen, että potilaita, joilla on suotuisa kasvaimen immunoprofiili(suuri määrä sytotoksisia T-soluja ja M1-tyypin makrofageja kasvaimen keskellä) pystyttäisiinhoitamaan keveimmillä hoidoilla ja HER2-hoitokeskeytys voisi olla mahdollinen näillä potilail-la. Lisäksi työ korostaa HER2- ja HER3-reseptorien kohdentamista syövän kantasolumaistensolujen tehokkaamman tuhoamisen saavuttamiseksi.
SDS-PAGE sodium dodecyl sulfate-polyacrylamide gel electrophoresis
SH2 Src homology-2
Shc Src homology-2 domain containing
shRNA short hairpin RNA
sgRNA single guide RNA
SOS son of sevenless
SOX2 sex determining region Y-box 2
TAM tumor-associated macrophage
T-DM1 trastuzumab emtansine
Th T helper
TGF-β transforming growth factor beta
TIL tumor infiltrating lymphocytes
TKI tyrosine kinase inhibitor
TLS tertiary lymphoid structure
TNF-α tumor necrosis factor alpha
TP53 tumor protein 53
TRAIL TNF-related apoptosis-inducing ligand
Treg regulatory T cell
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15
Original publications
This thesis is based on the following publications, which are referred throughout
the text by their Roman numerals:
I Honkanen, T.J.*, Moilanen, T.*, Karihtala, P., Tiainen, S., Auvinen, P., Väyrynen, J.P., Mäkinen, M. & Koivunen, J.P. (2017). Prognostic and predictive role of spatially positioned tumour infiltrating lymphocytes in metastatic HER2 positive breast cancer treated with trastuzumab. Sci Rep, 7(1), 18027.
II Honkanen, T.J., Tikkanen, A., Karihtala, P., Mäkinen, M., Väyrynen, J.P. & Koivunen, JP. (2019). Prognostic and predictive role of tumour-associated macrophages in HER2 positive breast cancer. Sci Rep, 9(1), 10961.
III Honkanen, T., Wilenius, E., Koivunen, P., & Koivunen, J.P. (2017). HER2 regulates cancer stem-like cell phenotype in ALK translocated NSCLC. Int J Oncol, 51(2), 599-606.
IV Honkanen T.J. & Koivunen J.P. (2019). HER3 regulates cancer stem-like cell properties in ALK translocated NSCLC. Manuscript.
*Equal contribution
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17
Table of contents
Abstract
Tiivistelmä
Acknowledgements 9
Abbreviations 11
Original publications 15
Table of contents 17
1 Introduction 19
2 Review of the literature 21
2.1 Cancer ..................................................................................................... 21
2.1.1 Cancer genetics ............................................................................. 21
2.1.2 Cancer epigenetics ........................................................................ 23
2.1.3 Cancer biology ............................................................................. 23
2.1.4 Main signaling pathways altered in cancer ................................... 27
2014). Thus, we assessed whether the genetic alterations of HER2 and HER3 had
an effect on the CSLCs by examining the expression of CSLC markers using
western blot analysis. As seen previously, ALK inhibition increased the expression
of CSLC markers, suggesting CSLC-mediated resistance. In the H3122 line, the
overexpression of HER2 did not change the basal ALDH1 expression but led to a
more pronounced increase in the expression in response to ALK inhibition. Basal
expression of CD44 was unaltered when HER2 was knocked down in H2228,
whereas the basal expression of ALDH1 was markedly downregulated. The
expression of CD44, however, was downregulated when ALK was inhibited. HER3
knockdown in H3122 did not change the basal expression of ALDH1 but
downregulated the basal expression of SOX2. The induction of ALDH1 expression
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in response to ALK inhibition was blocked when HER3 was knocked down, and
the induction of SOX2 was slightly downregulated by the knockdown.
The expression of the CSLC markers was even further increased in the control
cells and HER2 overexpressing cells when NRG1, a HER3 and HER4 ligand,
linked to tumor initiating cells, was introduced simultaneously with ALK inhibition.
A slight recovery of the CSLC marker downregulation in the HER2 knockdown
line was seen by the addition of NRG1 to ALK inhibition, but no changes were
seen in the HER3 knockdown cells, as expected.
5.2.3 The effects of the genetic alterations to cytotoxic response to
ALK inhibition
We investigated whether HER2 and HER3 alterations affected the cytotoxic
response of the cells to ALK inhibition by exploring their colony formation ability.
The main cytotoxic responses to ALK TKI remained unaffected by the alterations;
however, the overexpression of HER2 resulted in a slight increase in the number of
surviving colonies, and knockdown of HER2 or HER3 resulted in a slightly
decreased number of surviving colonies compared to the controls. The increased
survival in HER2 overexpressing cells was blocked by the addition of lapatinib
(targets EGFR and HER2) or afatinib (targets EGFR, HER2 and HER4) together
with the ALK TKI. No differences in the surviving colonies were seen between the
HER3 knockdown and control cells when afatinib or lapatinib was combined with
ALK TKI; however, the number of surviving colonies in HER2 knockdown cells
was decreased compared to the control cells.
More pronounced differences in the cytotoxic responses were seen when HER3
(and HER4) was activated with NRG1 treatment. NRG1 by itself did not alter the
colony formation abilities of the studied cells, however, when it was combined with
ALK TKI differences were seen between the HER2/HER3 altered cells and the
control cells. The addition of NRG1 to ALK TKI treatment increased markedly the
number of surviving colonies in the HER2 overexpressing cells, whereas only a
minor increase was seen in the control cells. No differences were seen between the
HER2 knockdown cells and the control cells when NRG1 was combined with ALK
TKI. The increased colony formation ability seen in the control cells in response to
NRG1 and ALK TKI was blocked by the knockdown of HER3.
The changes in the cytotoxic response to ALK TKI after HER2 alterations were
studied also with tumor sphere formation assay, which is a commonly used assay
to identify CSLCs in vitro. However, the assay was more like a colony formation
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assay with a CSLC-inducing environment for the H3122 cells, because the formed
spheres were cell rafts instead of spheres due to the cells’ ability to stick together
and difficulty in separating them properly. Despite that, the results from the assay
were similar to colony formation assay and CSLC protein expression patterns,
showing that HER2 knockdown diminished the survival of CSLCs if ALK was
inhibited, and the overexpression of HER2 increased the survival of CSLCs even
when ALK was continuously inhibited for 15 days.
5.2.4 Alterations in the Akt and ERK1/2 downstream signaling
The changes of HER2/HER3 alterations to the most common downstream signaling
pathways of RTKs, PI3K and MAPK were examined by studying the
phosphorylation of Akt and ERK1/2 proteins at 5h or 5 days after the initiation of
ALK inhibition. The alteration did not affect the initial (5h) response to ALK TKI;
instead, the differences were seen in the long-term (5 days) responses. HER2
overexpression in H3122 resulted in reformed downstream RTK signaling with
major upregulation of both phosphorylated Akt and ERK1/2, which was not seen
in the control cells. H2228 control cells were able to recover the downstream
signaling pathways after 5-day inhibition of ALK, which was blocked by the
knockdown of HER2. HER3 knockdown, however, hampered the Akt signaling
recovery, whereas ERK1/2 was able to recover similar to the control cells.
We examined the impact of NRG1 also on the downstream signaling pathway
recoveries. The addition of NRG1 with ALK TKI recovered the downstream
signaling of Akt and ERK1/2 in H3122 control cells, and the expression of
phosphorylated Akt was further increased in the HER2 overexpression cell line.
These signaling recoveries were blocked by the knockdown of HER3.
5.2.5 Compensatory expression of other HER family members
We examined whether the alterations of HER2 and HER3 affected the expression
and activation of the other HER family members. HER2 overexpression in H3122
cells led to an increased activation of EGFR, HER3 and HER4 proteins, of which
the activation of HER3 mimicked the expression patterns of the ALDH1, since the
most prominent activation of HER3 was seen when ALK was inhibited and NRG1
was provided, which also showed the most prominent expression of ALDH1. We
were unable to see activation of the HER proteins in the H2228 cell lines, but the
knockdown of HER2 downregulated the expression of HER3. In H3122 the HER3
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knockdown increased the phosphorylation of EGFR, but we were unable to see
activations of the other HER proteins in the control and in the HER3 knockdown
cells. The activation of EGFR was unable to recover the Akt signaling in the HER3
knockdown cells.
The addition of NRG1 was able to induce the activation of HER3 in HER2
overexpressed cells even when ALK was not inhibited, but more pronounced
activation was seen with a combinatory treatment of ALK TKI and NRG1, which
was also seen in H3122 control cells. Furthermore, ALK TKI together with NRG1
induced the strongest expression of CSLC markers.
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6 Discussion
There are many types of cancer treatments these days, such as surgery,
chemotherapy, radiation therapy, targeted therapy, and the latest newcomer,
immunotherapy. It is now well understood that one type of therapy is not suitable
for every patient, and precision medicine has taken its place in the field of oncology.
Targeted therapies, including small-molecule inhibitors and monoclonal antibodies,
and immunotherapy can be given to patients according to their tumor’s genetic
status. However, even though the genetics of the tumors appear to be suitable for
some specific therapy, not every patient will respond to the therapy, or the disease
will progress soon after the response due to development of an acquired resistance.
Many resistance mechanisms for different therapies have been discovered, for
example, the involvement of cancer stem-like cells that are resistant to different
therapies and are extremely tumorigenic. Unfortunately, cancer stem-like cells are
difficult to target, and there are no targeting agents available in the clinic. Therefore,
further research is needed to improve precision medicine in order to enhance patient
selection and develop new targeting agents or utilize the ones that are already
available.
6.1 Immunological markers in HER2+ breast cancer
The disease outcomes of HER2-positive breast cancers have dramatically improved
after HER2 targeting agents, like trastuzumab, became available (Marty et al., 2005;
Swain et al., 2015; Von Minckwitz et al., 2009). However, since its approval,
trastuzumab has been given according to the tumoral HER2 status only, and other
predictive factors for trastuzumab sensitivity or resistance are currently quite
uncharacterized. The mechanisms of action of trastuzumab are based on its ability
to bind the extracellular domain of HER2 and partially inhibit the signaling through
it, but the main effects of trastuzumab have been shown to be the activation of the
immune system through ADCC and ADCP (Clynes et al., 2000; Nami, Maadi, &
Wang, 2018; Petricevic et al., 2013). Some trastuzumab-resistance mechanisms
have been suggested, of course, such as alterations that abolish the signal
transduction inhibition of trastuzumab, like p95 variant of HER2, or alterations of
PTEN and PI3KCA and also compromised host immunoactivation, which prevents
the main effects of the antibody (Gagliato, Jardim, Marchesi, & Hortobagyi, 2016).
Among the metastatic HER2-positive breast cancers, great variation is seen in
treatment outcomes, with some patients surviving even more than 10 years with the
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disease (Moilanen et al., 2017). This is similar to what is seen with new cancer
immunotherapies; therefore, we speculated that the immunological status of the
tumor would play an important role in patient outcomes.
Our studies assessed whether the tumor-infiltrating immune cells evaluated by
using a quantitative computer-assisted counting method could be used as
prognostic and predictive markers in metastatic HER2-positive breast cancer
treated with trastuzumab. A larger number of patients could have been included in
the study if all the HER2-positive breast cancer patients were included. We selected
to study metastatic disease only, however, since this provides a more homogenous
population and better possibilities to study treatment effects. Furthermore, our
institute has pioneered in trastuzumab discontinuation in responding patients,
therefore providing a unique patient cohort to study factors associated with long
trastuzumab-free periods.
ADCC is mediated mainly through NK and T cells (Clynes et al., 2000; Park
et al., 2010), which were both studied in our retrospective patient material. Previous
studies have shown NK cell infiltration and activation in tumors after the
administration of trastuzumab to be associated with good trastuzumab responses
(Arnould et al., 2006; Tian et al., 2017). We studied the role of NK cells in
pretreatment samples and saw only a minor infiltration of the cells in our tumor
samples. A higher number of NK cells showed a tendency towards a better
prognosis, but the NK cell infiltration may not be optimal for predicting the clinical
outcomes in this subset of patients. It would have been interesting to see whether
the NK cells were able to penetrate the tumor tissue after administration of
trastuzumab, but unfortunately only a few patients had post-treatment samples
available, and the analysis was not performed. Furthermore, treatment decisions are
made based on the available patient and tumor characteristics, and post-treatment
markers provide less information for the clinical decision making.
T cell infiltration has been studied in many cancer types, and in colorectal
cancer the Immunoscore characterizing the abundance and location of CD3 and
CD8 positive T cells has been shown to be a powerful prognostic parameter (Galon
et al., 2014; Galon et al., 2006; Pagès et al., 2018). At the time of our studies, tumor-
infiltrating lymphocytes in HER2-positive breast cancers were studied mainly
using a morphological evaluation of the immune cells or measuring the immune
cell infiltrations in the whole tumor area. We studied the quantity of CD3 and CD8
positive T cells in the center of the tumors (CT) and in the invasive margin (IM)
separately and saw that a high number of the center tumoral CD3 or CD8 positive
T cells were significantly associated with improved outcomes, with the latter being
79
a more powerful prognostic factor. These results highlight the important role of
cytotoxic T cells in cancer eradication and that T cells in the CT and IM might
reflect different types of host immunoreaction to the tumor, which requires further
investigation. During the past few years, more studies on HER2-positive breast
cancer have been examining specific immune cell subtypes in different tumor
locations (in the center of the tumor or in the stroma) in patients treated with
trastuzumab (Hou, Nitta, Wei, Banks, Parwani et al., 2018; Liu et al., 2017; Takada
et al., 2018; van Rooijen et al., 2018). These studies have also confirmed the
importance of cytotoxic T cells in the disease.
Tumor associated macrophages (TAMs) are known to have clinical impact in
the tumor microenvironment, and the ADCP induced by trastuzumab is mainly
mediated by TAMs (Shi et al., 2015). However, little is known about the importance
and prognostic role of macrophages in HER2-positive breast cancer. We first
studied the TAMs using the CD68 marker, which did not give any significant
association with survival, although a high number of CD68 in the CT showed a
tendency towards improved prognosis. The CD68 marker also recognizes other
types of immune cells, not just macrophages, and because it is now well known that
there is a continuum of different macrophage phenotypes shifting from antitumoral
M1-like to pro-tumoral M2-like phenotype (Biswas & Mantovani, 2010; Brown et
al., 2017), we continued our studies using two distinct markers. Our studies
revealed that a high number of M1 polarized macrophages in both IM and CT show
a strong association with better outcomes and are consistent with previous works
studying breast, colorectal, ovarian and gastric cancers (Biswas et al., 2013;
Fridman et al., 2017), whereas the high number of M2 polarized macrophages
showed a tendency towards a poorer prognosis. Thus, our study supports the idea
of targeting the macrophage polarization in HER2-positive breast cancer, but
further investigation is required.
The tumor cells themselves can suppress the functions of the immune cells
required for the proper function of trastuzumab and other monoclonal antibodies,
and our results showed that the low tumoral expression of CD47 and IDO1 are
associated with improved patient outcomes, which were inconsistent with other
reports. CD47 is a commonly known inhibitor of phagocytosis, whereas IDO1 is
associated with an increased M2/M1 macrophage ratio, both of which lead to
immunosuppression and further highlight the importance macrophage-mediated
phagocytosis in tumor eradication (Jaiswal et al., 2009; Wang, X et al., 2014). Anti-
CD47 antibodies are already in clinical trials and have shown promising effects on
80
lymphomas with a favorable safety profile (Advani et al., 2018), while the clinical
trials are still ongoing in solid cancer.
One study (Loi et al., 2014) has shown that adjuvant trastuzumab efficacy is
limited to patients with high TILs. We therefore studied whether our most
promising prognostic markers, high number of CD8+ T cells in the CT and high
number of M1-like macrophages in the IM and CT, could predict the benefit from
trastuzumab in a metastatic setting. This analysis was rather difficult, since the
patients of our retrospective material were treated with trastuzumab at varying
points of their disease. Nevertheless, we selected the treatment length of the 1st
trastuzumab-containing regimen in a metastatic setting (surrogate of progression-
free survival) and the length of trastuzumab interruption in response as indicators
for the treatment benefit, based on the evidence from randomized trials and our
oncologists’ personal experience. In contrast to the recommended clinical protocols,
our institute has aimed to discontinue trastuzumab treatment if a metastatic HER2+
breast cancer patient has achieved a prolonged radiological response, and we have
seen that these patients can experience long trastuzumab-free periods (median of
51 months) without progression (Moilanen et al., 2017). We were unable to see a
connection between the length of the 1st trastuzumab treatment and the number of
CD8 positive CT cells alone, whereas M1 macrophages in the CT showed a
significant association. However, we saw an even more remarkable association
when we combined these markers. When we studied the patients whose
trastuzumab treatment was interrupted, a high number of all the three markers (CD8
CT, M1 CT, M1 IM) were associated with the length of trastuzumab discontinuation,
and the strongest association was seen with a combined analysis of CD8 CT and
M1 CT or IM status. Our results suggest that trastuzumab interruption could be
feasible for patients with a high CD8 CT and M1 status and that CD8 CT combined
with M1 CT should be further studied in the context of trastuzumab efficacy.
Our results support the idea of using distinct immune cell types in specific
tumor locations as prognostic and predictive markers for HER2-positive breast
cancer. However, it should be noted that different cancer therapeutics can alter the
immune cell composition of the tumors, for example, in a favorable way by
increasing the influx of cytotoxic cells but also in an unfavorable way by increasing
the influx of immunosuppressive cells into the tumor (Arnould et al., 2006;
DeNardo et al., 2011). A recent study additionally revealed that ADCP, induced in
TAMs by trastuzumab treatment, increases the expression of PD-L1 and IDO1 in
TAMs leading to immunosuppression (Su et al., 2018). This is quite
counterintuitive when considering the high impact and well-established benefit of
81
monoclonal antibodies in cancer therapies and should definitely be further studied.
Studying the immune cell infiltrations in trastuzumab-treated patients can be
challenging, because trastuzumab is received in combination with multiple
chemotherapeutic agents, which in turn can induce immunogenic cell death and
modulate the composition of immune cell prolife (Casares et al., 2005; García-
Martínez et al., 2014; Obeid et al., 2007; Parikh et al., 2014; Takahashi, Sakakura,
Mito, Ida, & Chikamatsu, 2016). Nevertheless, in the era of personalized medicine,
we need to be able to identify the patients who will or will not benefit from a
specific treatment. Trastuzumab is given to every breast cancer patient with HER2
amplification, even though it cannot be guaranteed that they will really benefit from
the therapy. Since adjuvant trastuzumab received in localized disease is a predictor
of poor prognosis in a metastatic setting (Moilanen et al., 2017; Murthy et al., 2012;
Rier et al., 2017), suggesting that acquired resistance to trastuzumab has been
developed, additional predictive markers for the patient selection are required.
6.2 The role of HER2 and HER3 for cancer stem-like cells in ALK
translocated NSCLC
HER proteins have been linked to cancer stem-like cells (CSLCs) in many cancer
types. NRG1, a HER3/HER4 ligand, has also been shown to induce CSLC features
in breast cancer (Ithimakin et al., 2013; Jeong et al., 2014; Korkaya et al., 2008;
Lee et al., 2014). CSLCs, in turn, have been linked to radiation therapy,
chemotherapy, targeted therapy and immunotherapy resistances, causing cancer
recurrence. CSLCs can prevent the therapeutic effects of monoclonal antibodies,
such as trastuzumab, by secreting immunosuppressive cytokines and modifying the
immune responses (Creighton et al., 2009; Maccalli et al., 2017; McLendon et al.,
2006; Phillips et al., 2006; Reim et al., 2009; Wang et al., 2017). The molecular
mechanisms behind the CSLC acquire are quite unknown, even though some
signaling pathways, like wnt/β-catenin, TGF-β and the HER2, have been linked to
it (Anido et al., 2010; Korkaya et al., 2009; Takebe et al., 2011). Several preclinical
studies and clinical trials are studying potential cancer stem-like cell targeting
agents, but none have been approved for cancer therapy (Li et al., 2017). A Phase
II study with ovarian cancer patients treated with chemotherapy and metformin, a
suggested CSLC targeting agent, showed a decreased number of ALDH+ CSLCs in
the tumors and increased sensitivity of the tumors to cisplatin in vitro (Buckanovich
et al., 2017). However, more data on the clinical utility of CSLC targeting agents
are urgently needed for the development of more efficient cancer treatments.
82
We assessed the significance of HER2 and HER3 for CSLCs in ALK
translocated NSCLC in studies III and IV. We chose to study ALK translocated
NSCLC because this disease represents a subgroup of patients who are extremely
sensitive to ALK inhibition but will inevitably develop a resistance to the treatment
within 1–2 years, which is common for targeted therapies (Peters et al., 2017;
Solomon et al., 2014). In addition, we have previously shown that CSLCs can
mediate the ALK tyrosine kinase inhibitor (TKI) resistance in the disease, and
several reports have linked the activation of bypass signaling via HER receptors to
the ALK TKI resistance (Doebele et al., 2012; Jokinen et al., 2014; Katayama et al.,
2012; Sasaki et al., 2011). Our results highlighted the importance of HER2 and
HER3 for CSLC-mediated ALK TKI resistance. Overexpression of HER2 resulted
in more pronounced expression of CSLC markers in response to ALK TKI, whereas
the knockdown of HER2 or HER3 inhibited this TKI-induced expression of CSLC
markers. The strongest expression of CSLC markers was seen when HER3 was
activated by NRG1, suggesting that CSLC-driven ALK TKI resistance could be
mediated via HER3 signaling. Even though NRG1 also activates HER4, it wasn’t
enough to restore the CSLC marker expression when HER3 was knocked down.
Moreover, our results pointed towards functionality of HER2 and HER3 to cancer
stem-like properties assessed by colony and sphere formation. HER2 and HER3
activation led to increased colony and sphere formation abilities, whereas the
knockdowns downregulated these capabilities. Our results support the idea of
blocking HER2-HER3 signaling to target CSLCs in order to inhibit the tumor
progression after cancer treatments.
HER2-HER3 is an important dimer signaling through PI3K and MAPK
pathways to sustain survival and proliferation of the cells. The HER3 part of the
dimer is essential for the PI3K pathway, since it can directly bind PI3K with its
several phospho-tyrosine residues, and HER2-amplified cancers have been shown
to depend on the HER3 signaling (Garrett et al., 2013; Lee-Hoeflich et al., 2008;
Schulze et al., 2005). HER2 and HER3 alteration of our studies did affect the
signaling through PI3K and MAPK pathways, with a more sustainable impact on
the former one. The overexpression of HER2 was able to reactivate the Akt and
ERK1/2 signaling after long-term exposure to ALK inhibition. This reactivation of
the signaling pathways, especially the Akt signaling, was blocked by the
knockdown of HER2 or HER3. In ALK translocated NSCLC, the Akt and ERK1/2
signaling are mainly driven by the ALK, and the recovery of the signaling pathways
after long exposure to ALK TKI is not entirely known. Our results demonstrate the
importance of HER2 and HER3 in this signaling recovery. Additionally, the
83
signaling recovery, after a long exposure to ALK inhibitor, is likely to reflect a
CSLC acquire in comparison to acute signaling changes that mirror the cytotoxic
responses, further highlighting the role of HER2 and HER3 for the CSLC
phenotype. The exact mechanisms of how HER2 and HER3 are activated after ALK
inhibition are unknown. It might be that the suppression of HER2 and HER3 by
negative feedback pathways is simultaneously inhibited when the downstream
signaling of ALK is blocked. Akt, for example, has been shown to mediate
suppression of HER3, and inhibition of Akt leads to increased expression and
phosphorylation of HER3 (Chandarlapaty et al., 2011). Moreover, the HER2 and
HER3 might not be the only RTKs that are upregulated when ALK is inhibited, as
seen in previous studies (Doebele et al., 2012; Katayama et al., 2012), and this
could be further studied.
Studies by others have shown that inhibition of one HER family member leads
to compensatory activation of other HER family members (Engelman et al., 2007;
Ritter et al., 2007; Yonesaka et al., 2011), which could be a major problem when
targeting these receptors therapeutically. Our results showed that HER2
overexpression can orchestrate the other members of the protein family.
Knockdown of HER3 increased the activity of EGFR; however, it was not enough
to reactivate the Akt signaling blocked by the knockdown. Our studies suggest that
targeting HER2 together with HER3 could be feasible for more efficient killing of
the cancer stem cells.
6.3 Implications of the results and future perspectives
The results of these studies provide suggestions for more efficient use of anti-HER
targeting agents. Our results with metastatic HER2-positive breast cancer patients
suggest that patients with a favorable tumor immune profile (low tumor expression
of CD47 and IDO1, high number of tumor-infiltrating CD8+ T cells and M1 TAMs
in the CT) might be treated in a less intensive manner and remain progression-free
during trastuzumab interruption, while patients with non-favorable immune profile
could be candidates for experimental immunotherapeutic approaches and more
effective cancer therapies should be developed for them (Fig. 7). These hypotheses,
however, must be confirmed in larger prospective studies but, if applicable, this
improved patient selection could lead to increased response rates and economical
savings. Our future studies will investigate further the impact of cytotoxic T cells
and M1-like macrophages utilizing in vitro ADCC and ADCP model. Because the
main mechanisms of action of trastuzumab depends on the activation of the
84
immune system, evaluation of chemokine profile in the tumor microenvironment
and the peripheral blood could be an interesting future study on the subject. A recent
work showed that HER2 signaling can recruit tumor-infiltrating immune cells by
inducing CCL2, which was important for the function of trastuzumab (Triulzi et al.,
2019). Another interesting perspective could be to study the gut microbiota, which
is extremely important for the proper function of the immune system and has been
shown to affect the immunotherapy responses (Routy et al., 2018; Vétizou et al.,
2015).
Since HER2 targeting agents have already been developed and are currently in
clinical use, and HER3 targeting agents are constantly being developed, the HER2-
HER3 dependency of CSLC-driven resistance revealed in our studies supports the
idea of investigating anti-HER agents as stem-like cell targeting agents in different
cancer types. This is not the first time HER proteins have been linked to CSLCs,
but our studies further support their targeting in combination with other treatments
to improve patient outcomes (Fig. 8). Studies combining HER3 targeting or NRG1
inhibitory agents with HER2 targeting agents should be studied in vitro and in vivo
in the future, and the significance of HER2-HER3 dimer could also be studied in
other diseases as well.
6.4 Limitations of the study
Our studies had some limitations. The number of tumor samples was low in
studies I and II, and patients were retrospectively collected from a single academic
cancer center. Patients included in studies I and II were all treated with trastuzumab,
which made the evaluation of the predictive values more challenging. Additionally,
most of the immune cell infiltrations were studied using only a single marker;
however, well characterized and widely used markers were selected for the studies.
Studies III and IV were performed only for two different cell lines, and only in vitro
models were used due to a restricted availability of cell line models of ALK
translocated NSCLC. The results of these studies should be confirmed with in vivo
models, even though it will be challenging.
85
Fig. 7. Main findings of our studies with HER2-positive breast cancer. Our results
suggest that patients with high infiltration of M1-like macrophages and CD8+ T cells in
the center of the tumor and low expression of CD47 and IDO1 in the tumor cells could
be treated less intensively, while more effective treatments are required for patients with
a less favorable tumor immune profile. ChT=chemotherapy.
CD47 highIDO1 high
CD47 lowIDO1 low
CD47 highIDO1 high
ChT +trastuzumab
Trastuzumabdiscontinuation
feasible in response
Trastuzumabdiscontinuation
not feasible
Immune cellinfiltrationshould beimproved
Cancer cell M1-like macrophage CD8+ T cell
86
Fig. 8. Schematic representation of dual targeting of ALK and HER2-HER3 dimer. Our
results suggest that expression of HER2 and HER3 is linked to cancer stem-like cells,
which are causing resistance to ALK TKI therapy and cancer recurrence. Dual inhibition
of ALK and HER2-HER3 dimer could improve cancer cell killing.
ALK TKI
HER2
HER2HER3
HER3
ALK TKI+ anti-HER2/HER3
HER2
HER2
Stem-like cell
Cancer cell
87
7 Conclusions
The current study investigated the possibilities of using HER targeting agents more
efficiently by selecting the HER2-positive breast cancer patients more accurately
for the trastuzumab treatment and by utilizing already available targeting agents to
target cancer stem-like cells. The following conclusions were made based on the
results:
1. A high density of cytotoxic T cells and/or M1-like macrophages in the center
of the tumor (CT) in the pretreatment tumor samples predicts a more favorable
outcome in metastatic HER2-positive breast cancer. The most significant
prognostic value is seen with a combinatory analysis of cytotoxic T cells and
M1-like macrophages.
2. A high density of cytotoxic T cells and M1-like macrophages in the CT can
predict the disease progression and the possibility of interrupting trastuzumab
treatment in metastatic HER2-positive breast cancer. This suggests that
patients with a favorable immune profile could be treated less intensively and
that more efficient treatments should be developed for patients with a low
density of cytotoxic T cells and M1-like macrophages in the CT.
3. An intense expression of CD47 and IDO1 in the tumor cells of HER2-positive
breast cancer is associated with more adverse outcomes, whereas a low
expression predicts more favorable outcomes.
4. HER2 and HER3 have significant roles for the cancer stem-like cell phenotype
in ALK translocated non-small cell lung cancer.
5. ALK tyrosine kinase inhibitor resistance can be mediated by HER2-HER3-
dependent cancer stem-like cells in ALK translocated NSCLC suggesting that
targeting the dimer together with the ALK inhibitor could be beneficial for
overcoming ALK TKI resistances and improving cancer treatments.
88
89
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Original publications
I Honkanen, T.J.*, Moilanen, T.*, Karihtala, P., Tiainen, S., Auvinen, P., Väyrynen, J.P., Mäkinen, M. & Koivunen, J.P. (2017). Prognostic and predictive role of spatially positioned tumour infiltrating lymphocytes in metastatic HER2 positive breast cancer treated with trastuzumab. Scientific Reports, 7(1), 18027.
II Honkanen, T.J., Tikkanen, A., Karihtala, P., Mäkinen, M., Väyrynen, J.P. & Koivunen, JP. (2019). Prognostic and predictive role of tumour-associated macrophages in HER2 positive breast cancer. Scientific Reports, 9(1), 10961.
III Honkanen, T., Wilenius, E., Koivunen, P., & Koivunen, J.P. (2017). HER2 regulates cancer stem-like cell phenotype in ALK translocated NSCLC. International Journal of Oncology, 51(2), 599-606.
IV Honkanen T.J. & Koivunen J.P. (2019). HER3 regulates cancer stem-like cell properties in ALK translocated NSCLC. Manuscript.
Reprinted with permission from Springer Nature (I, II) and Spandidos Publications
(III).
Original publications are not included in the electronic version of the dissertation.
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1514. Kotiaho, Antti (2019) Radiation dose determination using MOSFET and RPLdosimeters in x-ray imaging
1515. Hänninen, Sandra Lynn (2019) Transcriptional control of muscle cell excitation-contraction coupling : the role of activity and mitochondrial function
1516. Väyrynen, Otto (2019) Factors affecting aggressive oral tongue cancer invasionand development of in vitro models for chemoradiotherapy assay
1517. Euro, Ulla (2019) Risk factors for sciatica
1518. Lotvonen, Sinikka (2019) Palvelutaloon muuttaneiden ikääntyneiden fyysinentoimintakyky, sen muutos ja toimintakykyyn yhteydessä olevat tekijät ensim-mäisen asumisvuoden aikana
1519. Tuomikoski, Anna-Maria (2019) Sairaanhoitajien opiskelijaohjausosaaminen jaohjaajakoulutuksen vaikutus osaamiseen
1520. Raza, Ghulam Shere (2019) The role of dietary fibers in metabolic diseases
1521. Tiinanen, Suvi (2019) Methods for assessment of autonomic nervous systemactivity from cardiorespiratory signals
1523. Mällinen, Jari (2019) Studies on acute appendicitis with a special reference toappendicoliths and periappendicular abscesses
1524. Paavola, Timo (2019) Associations of low HDL-cholesterol level and prematurecoronary heart disease with functionality and phospholipid composition of HDLand with plasma oxLDL antibody levels
1525. Karki, Saujanya (2019) Oral health status, oral health-related quality of life andassociated factors among Nepalese schoolchildren
1526. Szabo, Zoltan (2019) Modulation of connective tissue growth factor and activinreceptor 2b function in cardiac hypertrophy and fibrosis
1527. Karttunen, Markus (2019) Lääkehoidon turvallinen toteuttaminen ikääntyneidenpitkäaikaishoidossa hoitohenkilöstön arvioimana
UNIVERSITY OF OULU P .O. Box 8000 F I -90014 UNIVERSITY OF OULU FINLAND
A C T A U N I V E R S I T A T I S O U L U E N S I S
University Lecturer Tuomo Glumoff
University Lecturer Santeri Palviainen
Senior research fellow Jari Juuti
Professor Olli Vuolteenaho
University Lecturer Veli-Matti Ulvinen
Planning Director Pertti Tikkanen
Professor Jari Juga
University Lecturer Anu Soikkeli
Professor Olli Vuolteenaho
Publications Editor Kirsti Nurkkala
ISBN 978-952-62-2343-8 (Paperback) ISBN 978-952-62-2344-5 (PDF) ISSN 0355-3221 (Print)ISSN 1796-2234 (Online)
U N I V E R S I TAT I S O U L U E N S I S
MEDICA
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D 1528
AC
TAT
iia Honkanen
OULU 2019
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Tiia Honkanen
MORE EFFICIENT USE OFHER TARGETING AGENTSIN CANCER THERAPY
UNIVERSITY OF OULU GRADUATE SCHOOL;UNIVERSITY OF OULU,FACULTY OF MEDICINE;MEDICAL RESEARCH CENTER OULU;OULU UNIVERSITY HOSPITAL