Targeting Myeloid Cells for Potential Cancer Therapies

Jingwen Pan

1,*

, Yida Zhang

2,#

, Wenkai He

3,#

and Yian Chen

Department of Bioengineering University of California San Diego, CA, U.S.A.

Truro High School Truro, Cornwall, U.K.

Shanghai Southwest Weiyu Middle School, Shanghai, China

IB program Beijing National Day School, Beijing, China

These two authors contributed equally to this work and should be considered as co-second authors

Keywords: Cancer, Myeloid Cells, CXCL12, Oral Squamous Cell Carcinoma, Positron Emission Tomography.

Abstract: Cancer is one of the major health concerns facing the global society. Though significant improvement in

cancer therapies have been done, further investigation into alternative treatment approaches are expected to

improve clinical outcomes. Myeloid cells are key components that shape the tumor microenvironment. The

distribution and recruitment of myeloid cells account for tumor progression and metastasis. Previous studies

provided evidence suggesting that the CXCL12/CXCR4 pathway is responsible for recruiting tumor-

supportive M2-type macrophages in the oral squamous cell carcinoma (OSCC) model, promoting

proliferation and spreading of OSCC cancer cells. CXCL12/CXCR4 pathway also actively affect other types

of tumors, like breast cancer. Thus, modifying CXCL12/CXCR4 interaction might be a potential target for

cancer treatment. Due to the lack of existing therapies targeting this pathway, we propose a potential treatment

targeting the CXCL12/CXCR4 pathway that binds monoclonal antibodies to CXCL12 ligands to eliminate its

expression in tumor sites. Positron emission tomography (PET) imaging enables the monitoring and

verification of the outcome of this novel design.

1 INTRODUCTION

Cancer, a collection of diseases characterized by an

abnormal cell that divides and spread into

surrounding tissues uncontrollably, is one of the

primary causes of death worldwide (World Health

Organization, 2021). Prevailing types of cancer

include oral squamous cell carcinoma (OSCC), breast

cancer, and melanoma. OSCC is the most common

cancer type that contributes to 95% of head and neck

cancers largely due to alcohol abuse and smoking

(Taghavi and Yazdi, 2015). Though advanced

treatments have been developed, the percentage of

patients who are alive five years after starting

treatment is still unsatisfactory due to the high

recurrence and metastasis rate (Taghavi and Yazdi,

2015; National Cancer Institute). Breast cancer is one

of the most often diagnoses among female cancer

patients and the leading cause of cancer mortality in

women (Akram, Iqbal, Daniyal, Khan, 2017). In

2012, around 1.7 million new cases were diagnosed

globally, accounting for 25% of all female cancer

cases (Breast cancer | world cancer research fund

international, 2021). Melanoma is a form of skin

cancer with a high incidence of metastasis that could

significantly reduce the survival rate (Davis, Shalin,

Tackett, 2019). Further understanding and

development of cancer mechanisms and treatments

are needed to boost patients' chances for survival and

recovery.

Myeloid cells are a vital component in the tumor

microenvironment (TME). They are derived from a

common myeloid progenitor in the human bone

marrow (Figure 1) (A., T. (n.d.), 2021). Tumor

growth is enhanced by myeloid cells since they

promote tumor angiogenesis, accelerate cancer cell

migration, and weaken the immune system (Schmid,

Varner, 2010).

Pan, J., Zhang, Y., He, W. and Chen, Y.

Targeting Myeloid Cells for Potential Cancer Therapies.

DOI: 10.5220/0011239000003438

In Proceedings of the 1st International Conference on Health Big Data and Intelligent Healthcare (ICHIH 2022), pages 173-180

ISBN: 978-989-758-596-8

173

Figure 1. Differentiation of myeloid lineage cells. In the bone marrow, myeloid progenitor cells are derived from

hematopoietic stem cells. And then myeloid progenitor cells differentiate into monocyte and neutrophils. Under pathological

conditions like cancer, myeloid-derived suppressor cells, which could further differentiate into tumor-associated

macrophages, would be generated as well. Macrophages could be induced to derive into either M1 or M2 macrophages. Figure

modified from (A., T. (n.d.). 2021).

Myeloid lineage cells comprise a heterogeneous

group of cells, including but not limited to

macrophages, neutrophils, and myeloid-derived

suppressor cells (MDSC). Tumor-associated

macrophages (TAMs) are the most copious tumor-

infiltrating myeloid cells that work in the innate

immune system and assist the initiation of adaptive

immunity (A., T. (n.d.). 2021). Based on their

functions in tumors and activations, macrophages are

classified into two main subsets: classically-activated

(M1) macrophages that show tumor-suppressive

functions and alternatively activated (M2)

macrophages that suppress the immune response and

facilitate tumor growth and invasion (Schmid, Varner

2010, Dandekar, Kingaonkar, Dhabekar 2011) . Since

TAMs have been proved to contribute to

immunosuppression and tumor invasion, the

mechanism of how TAMs are recruited to the tumor

sites is crucial to the development of potential cancer

immunotherapies (Dandekar, Kingaonkar, Dhabekar

2011).

Myeloid-derived suppressor cells (MDSC)

constitute a more recently discovered immature

myeloid cell population featured by the ability to

inhibit immune responses (Lv, Wang, Huang, 2019).

MDSC are widely considered as pro-tumorigenic in

solid tumors (Lv, Wang, Huang, 2019). These cells

demonstrate the pathological state of activation of

monocytes and relatively immature neutrophils.

Their prominent characteristic is the ability to inhibit

T cells' normal functioning, and consequently

promote the pathogenesis of various diseases (Veglia,

Perego, Gabrilovich, 2018).

Neutrophils are a type of granulocyte and belong

to the category of leukocytes. Granulocytes can be

classified by their performance under Wright's stain,

which is a hematologic stain that used for

distinguishing among blood cell types, into three

categories: neutrophils, eosinophils, and basophils, of

which neutrophils are the most common phagocytic

cells (Morris 2018, Wright stain 2020). The bone

marrow does not produce neutrophils directly at the

onset of infection, but first produces myeloid and

promyelocytes, which later differentiate into

neutrophils. After receiving the corresponding signal,

neutrophils travel through the bloodstream to the

infection and proceed to rapidly surround and engulf

the foreign material covered by complement and

antibodies (Brostjan, Oehler 2020).

Cancer-associated fibroblasts (CAFs), a type of

stroma cells that remodel the extracellular matrix, are

abundant in the tumor mesenchyme (Liu et al 2019,

Ping et al 2021). Accumulating studies indicate that

CAFs hinder the function of anti-tumor immunity via

their interaction with natural killer (NK) cells and T

cells (Li et al 2019). Furthermore, CAFs are

responsible for directing immunosuppressive cells

onto the tumor owing to their ability to secrete

various growth factors and proinflammatory

cytokines, such as CXCL12 (Liu et al 2019).

ICHIH 2022 - International Conference on Health Big Data and Intelligent Healthcare

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CAF-derived CXCL12 is a type of small molecule

chemokines that are distributed in assorted tissues.

Similar to other chemokines, CXCL12 along with its

chemokine receptor CXCR4 are key factors that

mediate the metastasis and proliferation of cancer

cells (Righetti 2019, Mollica Poeta, V., Massara, M.,

Capucetti, A., & Bonecchi, R. 2019). Recent studies

revealed that the activation of the CXCL12/CXCR4

pathway positively correlates with the recruitment of

TAMs to the tumor sites and the number of

monocytes differentiated into M2 macrophages

(Dandekar, Kingaonkar, Dhabekar 2011).

2 PREVIOUS MYELOID

CELLS-RELATED STUDIES

2.1 Myeloid Cell Profiles and

Immunotherapy Resistance

Mechanism

Kim et al. provide evidence that intrinsic tumor

pathways and mutual regulation between the

neutrophils and macrophages contribute to the

development of dichotomous myeloid (Mollica

Poeta, Massara, Capucetti, & Bonecchi 2019). The

dichotomous distribution between the macrophages

and neutrophils is observed by mouse breast cancer

models, found out that breast cancer can be divided

into 'hot tumors' (with rich immune cells) and 'cold

tumors.' And the 'hot' tumor could be further divided

into neutrophil-enriched subtypes (also known as the

NES) and macrophage-enriched subtype (MES)

group. The theory had been confirmed in human

breast cancer by analyzing the TNBC database (Kim

et al 2019).

Further, authors derived transcriptomic data sets

from various murine syngeneic mammary tumor

models and compared them to human breast cancer

data (Kim et al 2019). Kim et al. demonstrate that

human and murine cancers share many similarities.

But it is hard to control the immune

microenvironments with only one changing variable

in clinical trials (Kim et al 2019).

When breast cancer of NES and MES were

inoculated on both sides of mice, the different

subtypes will maintain their neutrophil and

macrophage frequencies, demonstrating the

formation of different myeloid subtypes are caused

by intrinsic tumor factors (Kim et al 2019). Thus, the

internal tumor factors could contribute to myeloid

cell profiles.

Some macrophages in different MES have high

signaling pathways that promote immune

suppression and promote tumor formation. In

contrast, others have increased the expression of

signaling pathways that promote the inflammatory

response (Kim et al 2019). And an increase in

monocytes is caused by the decrease in neutrophils

for NES.

Moreover, the ICB therapy had been found to

have a good effect on enriching MES in macrophages

with high expression of promoting inflammatory

responder signaling pathways. The ICB therapy has a

moderate impact on the enrichment of MES in

macrophages with increased expression of promoting

suppression of immune signaling pathways but could

improve the efficacy by combining CCR2KO and

ICB therapy. And no effect on NES at all as the

reduction of neutrophils hasn't enhanced the

effectiveness of ICB therapy for NES (Kim et al

2019).

The immunotherapy resistance mechanisms show

the importance of the immune microenvironment to

tumor heterogeneity. And provide a potential route in

improving the effectiveness of immunotherapy (Kim

et al 2019).

2.2 Promote Macrophage Recruitment

via the CXCL12/CXCR4 Pathway

CXCL12/CXCR4 pathway is one of the potential

mechanisms to actively recruits abundant

macrophages, especially pro-tumor M2

macrophages, that achieves the macrophage-enriched

feature.

The mechanism of how TAMs, especially tumor-

promoting M2 macrophages, migrate and accumulate

in the OSCC via the interaction between CAF,

CXCL12/ CXCR4 pathway, CSC, and M2

macrophages is demonstrated in a previous study (Li

et al 2019). In the research conducted by Li et al., an

in vivo test investigated the distribution and

phenotype of TAM in OSCC. Overexpression of

macrophages was observed in all OSCC samples

compared to normal and dysplasia specimens.

Besides, masses of these macrophages are pro-tumor

M2 (Li et al 2019). Using the human monocytic cell

line THP-1, resultant data shown that CAFs were

most efficient at recruiting THP-1 monocytes.

Among CAF-derived chemokines, the disparity

between expressions in normal cells and CAF cells

was the most significant for the CXCL12 chemokine

(24 folds) (Li et al 2019). All data from chemotactic

experiments suggested that CXCL12 was the

predominant chemoattractant to drive monocyte

Targeting Myeloid Cells for Potential Cancer Therapies

175

migration and recruitment (Li et al 2019). By labeling

two subtypes of TAM, tumor-suppressive M1 and

tumor-supportive M2, with distinct markers, the

genotype of macrophages that were differentiated

from THP-1 monocytes with the induction of CAF

was identified as M2 macrophages (Li et al 2019).

Besides, the cell viability assay demonstrated that M2

cells are crucial to promote proliferation and hinder

apoptosis of Cal-27 cancer cells (Li et al 2019). By

culturing Cal-27 cells with M2 macrophages, it was

confirmed that polarized M2 cells induce OSCC to

obtain the cancer stem cell-like characteristic. M2-

treated Cal 27 cells were further confirmed that M2

macrophages had high resistance to the

chemotherapy drug Vincristine (Li et al 2019). After

conducting both transwell invasion assay and wound-

healing assay to investigate the mobility of Cal 27

cells, the results revealed that M2 macrophages lead

to expedited metastasis of OSCC via epithelial-

mesenchymal transition (EMT) (Li et al 2019). In

short, CXCL12/ CXCR4 pathway is critical in

recruiting M2 macrophage polarization in OSCC,

resulting in enhanced cancer cell proliferation,

migration, and chemotherapy drug resistance.

2.3 Modified Labeling Method for

Visualization and Quantification of

MDSCs

Positron emission tomography (PET) is a nuclear

medicine technique that measures the metabolism of

cells in body tissues using tiny quantities of

radioactive chemicals called radiopharmaceuticals to

aid in the visualization of biochemical changes in the

body (Positron Emission Tomography (PET). (n.d.).

Thus, PET imaging is a powerful technique that

enables the visualization and monitoring of myeloid

cell distribution in TME (Hoffmann et al 2019). As

mentioned above, myeloid-derived suppressor cells

(MDSCs), a type of myeloid cells, are key

participants within the tumor microenvironment

(TME). Hoffman et al. applied an improved

intracellular cell labeling approach to quantify in

vitro-cultured MDSC motility in primary and

metastatic cancers in vitro (Hoffmann et al 2019).

Researchers labeled in vitro produced MDSCs from

polymorphonuclear (PMN-) and monocytic (M-)

subsets using a "

Cu-labeled 1,4,7-

triazacyclononane-tri acetic acid (NOTA)-treated

CD11b-specific monoclonal antibody (mAB)"

(Hoffmann et al 2019). Subsequent to transferring

them into primary and metastatic MMTV-PyMT

breast cancer and B16/F10 melanoma mouse models

respectively, PET and magnetic resonance images

can be acquired for visualizing and quantifying

MDSCs migrations (Hoffmann et al 2019). The

researchers also indicate that the

Cu-NOTA-

CD11b-mAB could be internalized within only 3

hours, resulting in moderately stable radiolabeling

with minimal detrimental influence on cell survival

and functionality. Furthermore, it was suggested by

researchers that CD11b-specific mAB can simply

adapt to label additional myeloid cells, including

monocytes, macrophages, or neutrophils, for in vivo

molecular imaging (Hoffmann et al 2019).

3 DISCUSSION

Besides OSCC, CXCL12/CXCR4 also impacts other

types of cancers. Breast cancer remained the most

frequent cancer among women globally, and it had

been revealed that the CXCL12 and CXCR4

signaling has been implicated in practically every

facet of breast cancer carcinogenesis (Zlotnik,

Burkhardt, & Homey 2011). Chemokines are

chemotactic cytokines and could be divided into

different subgroups. The subgroup that interacts with

their receptors could influence tumor growth and

metastasis (Mollica Poeta et al, 2019b, Eckert et al

2018). Several specific chemokine receptors are

found on both immune and tumor cells. And their

presence on cancer cells could aid in cancer diagnosis

(Jacquelot, Duong, Belz, Zitvogel 2018).

CXCR4 is a crucial signal in breast cancer

metastasis as it expresses high levels of CXCR4

ligand CXCL12 in many organs, including liver,

bones, lungs, and lymph nodes (Janssens, Struyf, &

Proost, 2018, Koizumi, Hojo, Akashi, Yasumoto, &

Saiki 2007, Balkwill 2004). By the presence of the

CXCR4 positive cells in breast cancer patients' lymph

nodes, the pDCs will secrete TNF, which induces

CXCR4 expression in their body, producing a high

expression of CXCL12 (Okuyama Kishima et al

2015). Besides, the CXCR4/CXCL12 pathway also

plays a vital role in the prevention of lung metastasis.

The CXCR2 ligands will recruit the CXCR2

neutrophils into the TME, where they will interact

with cancer cells and promote the expression of genes

implicated in metastasis (Yu et al 2016).

As described above, the CXCL12/CXCR4

pathway has a considerable effect on tumor

development, and therefore targeting the pathway

could illustrate a potent method to create innovative

therapy in cancer treatment. CXCR4 combines with

its ligand CXCL12 and then becomes able to activate

the downstream signaling pathway to boost cancer

development. Among the current workable therapies

ICHIH 2022 - International Conference on Health Big Data and Intelligent Healthcare

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targeting on CXCL12/CXCR4 pathway, CXCR4

inhibitors are the major direction of massive research,

because it is thought that CXCR4 antagonism can

prevent cancer from growing (Zhou et al 2018).

Plerixafor, also called "AMD3100", is the only

CXCR4 antagonist currently in clinical use (Zhou et

al 2018). Plerixafor is a tiny bicyclam molecule with

antiretroviral properties that could bind to CXCR4

(Zhou et al 2018). Since December 2008, it has been

made available to non-lymphoma Hodgkin's (NHL)

and multiple myeloma (MM) patients in the United

States (Zhou et al 2018). The vital function for

Plerixafor to prevent cancer development is

generated by its ability to block the signaling pathway

of CXCR4 after binding to CXCR4. However, this

drug still has some deficiencies. Plerixafor lacks

CXCR4 specificity. Research has demonstrated that

Plerixafor only competes for CXCL12 binding to

CXCR4 when high quantities of Plerixafor are

present, indicating that Plerixafor is a low-affinity

CXCR4 ligand. Plerixafor promotes CXCL12

binding to CXCR7 and triggers the CXCL12/CXCR7

signaling pathway (Kalatskaya 2009). Therefore, it is

necessary to find other efficient treatment targeting

on CXCL12/CXCR4 pathway.

4 POTENTIAL NOVEL

TREATMENT

Owing to the lack of well-developed treatment

targeting the CXCL12/CXCR4 interaction approved

for clinical use, we herein propose a potential

treatment that is based on the use of anti-CXCL12

monoclonal antibody (mAB) for OSCC. Fig.2

illustrates that CXCL12 mAB would bind to

CXCR12; thus, preventing CXCL12 from interacting

with CXCR4 receptor. It's expected to see reduced

migration and expression of M2 macrophages in

tumor sites with the anti-CXCL12 treatment.

Figure 2. The CXCL12 mAB is expected to bind to

CXCL12, which would prevent it from interacting with its

receptor CXCR4 located on the cell surface. Figure

modified from (Cancilla, Rettig & DiPersio 2020).

By using animal models, in vitro experiments are

able to represent the whole organism with

physiological relevance and the inherent complexity

of a living system (Katt, Placone, Wong, Xu &

Searson 2016). Due to the fact that mice are cheap,

easy to breed, and biologically similar to humans,

mice are the desired animal models to be used in this

proposed design (Bryda 2013). OSCC-bearing Balb/c

mice models can be established from the murine

squamous cell carcinoma cell line, SCC7, which is

indicated to result in stable syngeneic OSCC models

in a previous study (Li 2020). Due to its ability to

recognize CXCL12 in both human and mice models,

monoclonal antibody (mAB) MAB350 (R&D

Systems, Inc) is selected to test the hypothesis that

neutralizing CXCL12 ligands is capable of reducing

M2 macrophage recruitments and treating OSCC in

the living organism (Human/Mouse CXCL12/SDF-1

antibody. 2020). The negative control is achieved

with no injection of MAB350 into mice, while the

experimental group is peritumoral injected with anti-

CXCL12 antibodies. Peritumoral injection would

prevent artificial injury to surrounding tissues by the

needle (Yoshida 2018).

The effect of injected mAB can be identified and

visualized via PET imaging. Tumor-associated

macrophages with the specific pro-tumor M2

phenotype could be cultured in vitro following the

instructions mentioned in Rey-Giraud et al.'s study. In

brief, freshly isolated monocytes would be cultured

in XVivo 10 media with M-CSF for six days to allow

for the generation of monocyte-derived M2

macrophages (Rey-Giraud, Hafner & Ries 2012). The

fact that CD11b is a common surface protein

expressed on both human and murine macrophages

makes CD11b a great target for radiolabeling

(Dziennis et al 1995). The procedure to radiolabel in

vitro-generated M2 macrophages is adapted from

Sabrina et al. In short, M2 macrophages are incubated

with [

Cu]NOTA-αCD11b-mAb in PBS media for

half an hour at 37℃ (Hoffmann et al 2019).

Radiolabeled M2 macrophages are then transferred

into OSCC-bearing mice models for PET imaging.

For 2hr, 4hr, and 12hr after injection of anti-

CXCL12 mAB, a PET scan would be acquired for

each mice model (InveonTM user manual: Inveon

scanners and inveon acquisition workplace 1.5 with

service pack 1. 2011). By quantitatively analyzing

and comparing the signal of the PET images, we

might be able to examine the migration of labeled M2

macrophages to the OSCC tumor sites. Since the

expression of M2 macrophages is confirmed to

correlate with tumor progression positively, lower

levels of M2 macrophages are expected in anti-

Targeting Myeloid Cells for Potential Cancer Therapies

177

CXCL12 mAb-treated mice models (Li et al 2019).

The negative control is estimated to have a much

higher expression of M2 macrophages than all

experimental models. Results that match our

expectations could verify our hypothesis that

potential cancer treatment targeting on

CXCL12/CXCR4 pathway; specifically, the use of

anti-CXCL12 antibodies is a feasible therapy.

5 CONCLUSIONS

Briefly, based on different characteristics of various

myeloid cells and previous myeloid cells-related

studies, the CXCL12/CXCR4 pathway was used as

an entry point to identify viable therapies for this

pathway, namely the use of Plerixafor (Righetti 2019,

Kim et al 2019). Due to drawbacks of Plerixafor, it is

necessary to continue searching for alternative

therapeutic approaches targeting the

CXCL12/CXCR4 pathway. Herein, a potential

cancer treatment pathway is proposed: by developing

CXCL12 inhibitors, the migration and expression of

M2 macrophages at the tumor site are reduced. This

treatment can be done as a further test in humans after

the effects are confirmed in animal models.

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