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RESEARCH 

Notch as an Immunologic Basis of Cancer 

Disparities 
Portia LaLiah Thomas1,2,3 and Anil Shanker1,3,4,5,*1 

1Department of Biochemistry, Cancer Biology, Neuroscience and Pharmacology, School of Medicine, 

Meharry Medical College, Nashville, TN, USA 2Department of Microbiology, Immunology and Physiology, 

School of Medicine, Meharry Medical College, Nashville, TN, USA 3School of Graduate Studies and 

Research, Meharry Medical College, Nashville, TN, USA 4Host–Tumor Interactions Research Program, 

Vanderbilt-Ingram Comprehensive Cancer Center, Vanderbilt University School of Medicine, Nashville, TN, 

USA 5Vanderbilt Institute for Infection, Immunology and Inflammation, Vanderbilt University School of 

Medicine, Nashville, TN, USA 

*Corresponding author: Email: ashanker@mmc.edu 

ABSTRACT 
Inter-individual differences due to racial/ethnic backgrounds may alter host immunity responsible for the 

cancer immunosurveillance and elimination, leading to disparate cancer incidence and relapse. One 

basis of disparity in tumor incidence, progression or therapeutic outcomes could lie in the components 

of Notch intercellular communication system, which provide instructive signals for a variety of pathways 

regulating cell commitment and differentiation including context-dependent lymphocyte polarization in 

tumor microenvironment. Notch signaling in hematopoietic cells is perturbed by tumor growth for its 

advantage, and there are indications that differences in Notch components could underlie poor cancer 

prognosis in certain populations. Here, we discuss the oncogenic and immunologic aspects of Notch, 

which should inform on cancer health disparities and therapeutic outcomes. 

 

KEYWORDS: Cancer immunity, Health disparity, Notch, Lymphocytes, Immunosurveillance, 

Immunotherapy 

 

Citation: Thomas PL, Shanker A (2019) Notch as an Immunologic Basis of Cancer Disparities. Cancer Health 

Disparities 3: e1-e-10. doi:10.9777/chd.2019.1006. 



 
 
 
 
 

 

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INTRODUCTION 

Immunologic basis of racial disparities 

Racial disparities in cancer are well documented in 

various solid cancers. This disparity is particularly 

evident in breast cancer, where paradoxically, the 

mortality rates in African-American compared to 

White American/Caucasian women are considerably 

higher despite lower lifetime incidence rates of 

breast cancer (Fregene and Newman, 2005; 

Howlader et al., 2018). Although many differences in 

breast cancer incidence/outcome can be explained 

by socioeconomic disadvantages, recent studies 

have broadened our understanding of the 

correlation of genetic mutations and ancestry with 

race/ethnic-associated disparities. It is crucial to note 

that genetics not only affects cancer susceptibility but 

the immune response to cancer as well. It has long 

been recognized that lymphocytes, specifically 

natural killer (NK) cells and T cells, differ significantly 

in their ability to mediate effector responses 

depending on the genetic constitution of an 

individual. The major histocompatibility and the 

leukocyte receptor complexes are the two most 

polymorphic regions of the immune genome. 

Individuals with increasingly diverse repertoires of 

MHC class-I molecules have a greater potential for 

their NK cells to be more responsive. This is evident 

from the differential susceptibility of some individuals 

to HIV infection and their wide range of 

asymptomatic phase (Kulkarni et al., 2009; Martin et 

al., 2018; Ramsuran et al., 2018). The underlying 

mechanism of the differences in lymphocyte effector 

responses against tumor in disparate populations 

could involve differential expression of inhibitory and 

activating receptors on lymphocytes. One of these 

receptors belongs to the Notch family, which offers a 

major juxtacrine signaling system that allows cellular 

crosstalk to program almost every cell type in the 

body.  

Notch signaling is highly conserved evolutionarily as it 

is important for cell-to-cell communication for tissue 

patterning during embryonic development. Mammals 

express four Notch receptors (Notch 1-4), which can 

bind to five canonical transmembrane ligands from 

two paralogous gene families– Delta-like (DLL1, DLL3, 

DLL4) and Jagged (JAG1 and JAG2) (Andersson et al., 

2011; Radtke et al., 2010; Yuan et al., 2010). The Delta 

ligands transactivate Notch amongst neighboring cells 

and cis-inhibit Notch in its own cells following receptor 

engagement (Crabtree et al., 2016; Sprinzak et al., 

2010; Yaron and Sprinzak, 2012). The receptor-ligand 

interaction between juxtaposing cells initiates a 

cascade of events involving transendocytosis, 

proteolytic cleavages, ubiquitination and 

deubiquitination transforming the cell surface receptor 

into a nuclear factor acting on the transcription of 

several target genes. Briefly, a conformational change 

in the ligated receptor exposes the S2 cleavage site 

(12–13 amino acids external to the transmembrane 

domain) for proteolysis by metalloproteases of the -

disintegrin-and-metalloproteinase (ADAM) family. The 

Notch extracellular domain is shed and endocytosed 

by the ligand-expressing cell (Radtke et al., 2010). After 

shedding, the transmembrane domain is cleaved at 

the S3 site by secretase freeing the Notch 

intracellular domain (NICD). The NICD subsequently 

traffics to the nucleus, heterodimerizing with DNA 

binding transcription factor CBF1/suppressor of 

hairless/LAG-1 (CSL). The C promoter-binding factor 

(CBF1) in humans is also known as recombination 

signal binding protein for immunoglobulin  J region 

(RBPJ-) or -binding factor 2 (KBF2) in mice, as 

suppressor of hairless [Su(H)] in Drosophila and 

longevity-assurance gene-1 (LAG-1) in Caenorhabditis 

elegans. The CSL-bound NICD recruits various 

coactivators, including mastermind proteins (MAML1-

3), inducing transcriptional expression of Notch 

downstream target genes hairy enhancer of split 



 
 
 
 
 

 

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(Hes1) and hairy related (Hey1 or Hrt). Notch signaling 

can also crosstalk with other signaling pathways such 

as NF-B and TGF- widening the Notch 

downstream target genes involved in effector T cells 

(Kuijk et al., 2013; Radtke et al., 2010; Yuan et al., 2010). 

Promiscuous receptor-ligand binding makes Notch 

signaling highly dose- and context-dependent (Previs 

et al., 2015).  

Notch can contribute to tumorigenesis if partnered 

with another onco-signaling, or can improve 

antitumor lymphocyte function if presented with the 

right repertoire of Notch receptor-ligands in the 

tumor microenvironment (Biktasova et al., 2015; 

Huang et al., 2011; Lobry et al., 2011). There are 

indications that differences in Notch components 

could underlie poor disease prognosis in certain 

populations. Based on data from the chronic 

obstructive pulmonary disease (COPD) clinical trial 

NCT00774176, the expression of mastermind-like 

protein 1 (MAML1), which affects Notch-dependent 

angiogenesis in lung, was found to be associated 

with COPD exacerbation in African Americans (Busch 

et al., 2016). As per The Cancer Genome Atlas 

(TCGA) data, a novel Notch protein, Notch 2 N-

terminal like protein (NOTCH2NL/N2N), was found 

to be increased in breast cancer tissue of African-

Americans relative to Caucasians. Correspondingly, 

disparities in Notch signaling can impact cancer 

development and therapy as discussed below. 

NOTCH IN CANCER DEVELOPMENT 

Although Notch signaling plays a crucial role in 

embryonic development, tissue homeostasis, cell 

proliferation, apoptosis, hematopoiesis, as well as 

differentiation and function of various immune cells 

including lymphocytes, dysregulation of Notch 

signaling leads to several diseases, including cancer 

(Radtke et al., 2010; Yuan et al., 2010). For instance, 

crosstalk between TGF-β and Notch is essential for 

epithelial-mesenchymal transition (EMT) as Notch 

signaling is needed to sustain the expression of TGF-

β-induced Notch target gene Hey1, which acts as a 

transcriptional repressor (Klinakis et al., 2011). 

Deregulation of the Notch pathway can occur by 

various mechanisms including overexpression, 

mutational activation or inactivation, posttranslational 

modifications and epigenetic regulation 

(Ntziachristos et al., 2014). 

Notch signaling in breast cancer progression 

Notch signaling drives many human hematologic 

and solid malignancies including breast cancer, 

medulloblastoma, colorectal cancer, lung cancer and 

melanoma (Ntziachristos et al., 2014). Notch 

signaling plays a central role in breast cancer 

development and progression by promoting tumor 

growth, invasiveness and metastasis (Previs et al., 

2015). Increased expression of NOTCH1 and 

NOTCH3 receptors have been associated with triple-

negative breast cancer (TNBC). NOTCH4 

overexpression has been correlated with hormone-

receptor positive breast cancer. On the contrary, 

NOTCH2 has been associated with better survival 

(Parr et al., 2004). In addition, NOTCH1 has lowered 

expression in HER-2 positive breast cancers 

(Touplikioti, 2012). Studies also indicated that high 

NOTCH1 and JAG1 in breast cancer patients 

correlated with poorer overall survival (Reedijk et al., 

2005). Recently, NOTCH1, NOTCH3 and JAG1 were 

shown to be at the nexus of a vicious cycle of 

macrophage infiltration into basal-like breast cancers 

by regulating the expression of proinflammatory 

cytokines, IL-1β and CCL2, thus increasing cancer 

invasiveness (Shen et al., 2017).  

Notch signaling in lung cancer progression 

Notch signaling plays an integral role in lung cancer 

initiation and progression. In non-small cell lung 



 
 
 
 
 

 

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cancer (NSCLC), Notch signaling crosstalks with 

various transcription factors to enhance EMT during 

cancer development. Blockade of Notch signaling 

inhibits progression and migration of NSCLC by 

reversing EMT (Xu et al., 2018; Yuan et al., 2014). In a 

wide variety of lung cancer patients (squamous cell 

carcinoma, adenocarcinoma, transitional cell 

carcinoma and large cell carcinoma) expression 

levels of Delta-like Notch ligands DLL1 and their 

target gene HES1 were significantly altered in 

hematopoietic compartment by tumor-derived 

factors. These changes in Notch components were 

reproduced in various murine cancer models 

including lung cancer. The decreased expression of 

Notch components resulted in tumor-induced 

immunosuppression in T cell function that correlated 

with poor prognosis (Biktasova et al., 2015; Huang et 

al., 2011; Thounaojam et al., 2015). 

NOTCH BASIS OF CANCER DISPARITIES 

Expression of Notch in breast cancer is subtype-

dependent 

Although the role of Notch in cancer initiation and 

progression is known, its contribution to cancer 

disparities has not been explored. The plausible 

effect of Notch on cancer disparities, however, can 

be seen in breast cancer where more aggressive 

subtypes known to disproportionately affect minority 

populations have differential Notch signaling than 

less aggressive types (hormone-receptor positive). 

Overexpression of Notch target gene HES1, -

secretase protein presenilin-1 (PSEN1), and lunatic-

fringe (LFNG) – a β3N-acetylglucosaminyl-tranferase, 

which regulates ligand-mediated activation of the 

Notch pathway – were found to be favorable for 

disease-free survival in luminal type A breast cancer. 

Overexpression of these same Notch genes, 

however, was unfavorable for disease-free survival in 

TNBC as analyzed in the TCGA breast cancer cohort 

(Orzechowska et al., 2017). In a study using next 

generation sequencing to identify Notch mutations 

in solid tumors, only TNBCs showed NOTCH1 and 

NOTCH2 rearrangements which led to constitutive 

receptor activation (Stoeck et al., 2014). These studies 

provide evidence of distinct Notch signaling profiles 

in various breast cancer subtypes, which also have 

known racial disparities of incidence and outcome. 

Findings suggest that the differential expression of 

Notch components can affect breast cancer 

progression and elucidate response to treatment.  

Expression of Notch2N in breast cancer is race-

dependent 

A novel Notch protein, Notch 2 N-terminal-like 

protein (NOTCH2NL/N2N), has been found to be 

highly upregulated in breast, colorectal, and prostate 

cancer as reported in The Cancer Genome Atlas 

(TCGA). Notably, African-Americans show an increase 

in N2N expression in breast cancer relative to 

Caucasians (p = 0.0037), per TCGA database (Fig. 1).  

 

Figure 1. Expression of Notch 2 N-terminal like (N2N) 

RNA as a predictor of breast cancer disparities. 

Genomic data available in The Cancer Genome Atlas 

(TCGA) were used to analyze N2N gene expression 

of breast cancer tissues from African Americans  

(n = 41) in comparison with Caucasians (n = 423). 

*Unpaired two-tailed t-test with Welch’s correction. 



 
 
 
 
 

 

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In vitro, N2N has been shown to repress the 

transcriptional activities of Notch 2 and Notch 1 

intracellular domains, which are important for 

antitumor lymphocyte effector function and memory 

(Biktasova et al., 2015; Huang et al., 2011; 

Thounaojam et al., 2015). Thus, N2N could be a 

possible predictive candidate for cancer disparities 

and poor prognosis amongst the African-American 

population. N2N has also been shown to be 

targeted by neutrophil elastase and implicated in 

hereditary neutropenia (Duan et al., 2004). 

ROLE OF NOTCH IN CANCER IMMUNITY 

Notch signaling in T lymphocytes 

It is well established that tumor-induced immune 

suppression by multiple mechanisms is a major 

impediment to the success of cancer therapy. An 

intact functional immune system is required for the 

induction of sustained tumor regression upon 

inactivation of the tumor-driving oncogenes (Rakhra 

et al., 2010). The generation of effector CD8+ T cells is 

imperative for antitumor immunity (Kuijk et al., 2013; 

Thounaojam et al., 2015; Uzhachenko and Shanker, 

2016). The Notch signaling pathway plays an 

important role in the regulation of differentiation and 

function of lymphocytes, while being extremely 

pleiotropic with an interrelated network of receptor-

ligand interactions. Most gain-of-function studies 

indicate that Delta-like ligands promote CD4+ T cell 

commitment to Th1 (Amsen et al., 2009; Amsen et 

al., 2004). Although controversy exists, the bias is that 

Jag ligands associate with Th2-promoting Notch 

function (Amsen et al., 2009; Krawczyk et al., 2008). 

Notch has also been reported to associate with the 

regulation of IL17 and RORt gene promoters to 

influence Th17 differentiation (Keerthivasan et al., 

2011). In addition to promoting Th1, Th2 and Th17 

differentiation, some Notch ligands, on the contrary, 

play an immunosuppressive function. Expression of 

Jag ligands by antigen-presenting cells or 

hematopoietic progenitors favored generation of 

suppressive T cells in vitro and regulatory T cells 

(Treg) in vivo (Kared et al., 2006; Vigouroux et al., 

2003; Yvon et al., 2003). In addition, expression of 

Delta-like Notch ligands in hematopoietic 

compartment is significantly altered by tumor-

derived factors resulting in tumor-induced 

immunosuppression (Biktasova et al., 2015; Huang et 

al., 2011; Thounaojam et al., 2015). Systemic blockade 

of Jag1/2 or DLL1 overexpression overcame tumor-

induced T cell tolerance suggesting the involvement 

of these ligands in anti-tumor T cell function (Huang 

et al., 2011; Palaga et al., 2003; Sierra et al., 2017). 

Evidence supports that Notch signaling promotes 

differentiation of naïve CD8+ T cells into cytotoxic 

and memory T lymphocytes by upregulating the 

transcription factor Eomesodermin responsible for 

regulating expression of effector molecules IFN, 

granzymes, and perforins (Biktasova et al., 2015; 

Palaga et al., 2003; Radtke et al., 2010; Sauma et al., 

2012; Thounaojam et al., 2015; Tsukumo and 

Yasutomo, 2004). Conditional transgenic expression 

of Notch 1 intracellular domain in CD8+ T cells 

induces maturation towards a central memory 

phenotype (Sierra et al., 2014). In murine CD8+ T 

cells, Notch signaling controls activated CD8+ T cell 

fate towards terminal effector cell versus memory 

precursor cell fates (Backer et al., 2014). Studies also 

noted that Notch1/2 signaling was associated with 

increased IL-2 synthesis and upregulated expression 

of IL-2 receptor  chain, CD25 on T cells and 

inhibition of Notch signaling resulted in decreased 

proliferation of CD4+ and CD8+ T lymphocytes (Adler 

et al., 2003; Thounaojam et al., 2015). In addition, 

treatment of tumor-bearing mice with cancer 

therapeutic drug bortezomib, a proteasome 

inhibitor, enhanced expression of Notch signaling 

components in lymphoid tissues resulting in CD8+ T 



 
 
 
 
 

 

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cell expression of effector molecules, perforin and 

granzyme B as well as IFN-secretion (Thounaojam 

et al., 2015). Furthermore, there appears to be a 

consensus in the published data to suggest that 

Notch 1 and Notch 2 are key players in the induction 

of cytolytic and memory T cell function (Auderset et 

al., 2012; Biktasova et al., 2015; Huang et al., 2011; 

Laky et al., 2015; Sierra et al., 2014; Sugimoto et al., 

2010; Thounaojam et al., 2015).  

Recently, it was shown that Notch 1 activation could 

occur in peripheral T cells in a ligand-independent 

manner through chemical adjustments in the 

endosome within a few hours post-TCR stimulation 

(Steinbuck et al., 2018). Alternatively, Notch 1/2 may 

fine-tune the sensitivity, magnitude and quality of the 

T cell response by promoting metabolic 

reprogramming besides specifying lineage choice or 

controlling expression of regulators following the 

initial steps of antigen encounter by T cells (Laky et 

al., 2015). Also, it is known that a transient pulse of a 

high level of Notch 1/2 cognate Delta-like ligand is 

capable of inducing Hes1 expression for a duration 

that is sufficient to induce a binary cell fate switch. 

For example, transient DLL-Notch signaling has been 

shown to be sufficient to induce T cell (Lefort et al., 

2006) or NK cell differentiation (Carotta et al., 2006). 

Notch signaling in NK cells 

Human studies indicate that Notch 1 signaling is 

crucial for NK cell maturation and effector function as 

well, with an increase in Notch 1 signaling leading to 

an enhanced inhibitory killer immunoglobulin-like 

receptor (KIR) expression on NK cells. Augmented 

Notch 1 signaling also induces increased cytolytic 

effector capacity and cytokine secretion of human 

peripheral NK cells, enhancing their antitumor 

functions (Felices et al., 2014). Furthermore, an 

increase in Notch signaling by miR-181 increases 

production of IFN- in primary NK cells (Cichocki et 

al., 2011). In murine studies, dendritic cell 

overexpression of Notch ligand Jag2, which signals 

through Notch 2, directly enhances NK cytotoxicity, 

IFN-production, and proliferation (Kijima et al., 

2008). From these studies, it is evident that Notch 

signaling apparatus is critical not only for T cell 

effector and memory functions but also for NK cell 

function. 

OVERCOMING TUMOR INTERFERENCE 

WITH LYMPHOPOIETIC NOTCH 

Given the critical roles of Notch in providing 

instructive signals for T cell and NK cell differentiation 

and function, it is logical to consider that tumors will 

interfere with Notch signaling in lymphocytes to 

promote and sustain tumor growth. Indeed, tumors 

downregulate or perturb Notch signaling in 

lymphocytes to escape immune surveillance. 

Moreover, tumors tend to alter the expression of 

Notch ligands as a prominent mechanism of 

immunosuppression in conjunction with elevated 

circulating levels of vascular endothelial growth 

factor (VEGF) (Huang et al., 2011; Novitskiy et al., 

2010). In particular, tumors specifically downregulate 

expression of Delta-like ligands DLL1 and DLL4 in the 

tumor microenvironment to escape from T cell-

mediated immunity (Biktasova et al., 2015; Huang et 

al., 2011; Thounaojam et al., 2015). Restoring the 

cognate Notch receptor signaling by enhancing the 

availability of DLL1 by endogenous overexpression or 

pharmacological administration of clustered 

multivalent DLL1 leads to improved tumor rejection 

(Biktasova et al., 2015; Huang et al., 2011). 

Furthermore, tumor-bearing mice following 

treatment with the proteasome inhibitor bortezomib, 

showed increased CD8+ T lymphocyte IFN- 

secretion and perforin and granzyme B expression 

by enhanced Notch-NF-B signaling crosstalk 

(Thounaojam et al., 2015; Uzhachenko and Shanker, 



 
 
 
 
 

 

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2016). Thus, for effective treatments and addressal of 

disparities in cancers, immunotherapeutic strategies 

would need to overcome tumor-induced Notch-

based immunosuppression. 

CONCLUDING REMARKS AND FUTURE 

PERSPECTIVES 

Although much remains to be learned about key 

aspects of Notch basis of cancer disparities, available 

evidence is clear to suggest that Notch signaling is 

crucial for antitumor lymphocyte effector and 

memory functions. Notch signaling is perturbed in 

hematopoietic cells by tumor growth for its 

advantage, and there are indications that differences 

in Notch components could underlie poor cancer 

prognosis in certain racial/ethnic populations. Due to 

the heterogeneity of Notch signaling in tumors and 

the potential for Notch to be onco- and tumorigenic 

on one hand and lymphostimulatory on the other, 

racial disparities in cancer may be addressed through 

systematic elucidation of following profiles. 

(1) Characterizing the Notch profiles of various 

cancer subtypes and tumor-infiltrating immune cells 

in various racial/ethnic populations should serve to 

provide a useful resource for understanding Notch-

based tumor-immune interactions in the tumor 

microenvironment. (2) Understanding the inter-

individual host factors that influence naturally 

occurring lymphocyte responses will also be an 

important prerequisite to understand the host 

immune responsiveness and design a successful 

immunotherapeutic modality. In contrast to our 

understanding of the naturally occurring immune 

responses to many infectious agents, our knowledge 

of the immunogenetic factors that influence immune 

responsiveness to tumor-associated antigens is vastly 

incomplete. (3) An improved understanding of the 

immunogenetic mechanisms underlying T cell and 

NK cell immunity in disparate racial/ethnic 

populations will be helpful in designing efficient 

personalized immune strategies against cancer. This 

knowledge would also be instrumental in the proper 

evaluation of lymphocyte-based immunotherapy 

trials as some people could be naturally high 

responders to adoptive cell immunotherapy, while 

others could be low responders. This possibility, 

unless taken into account, could confound the 

evaluation of immunotherapy trials. (4) Based on the 

outcomes of these studies, it will, then, be important 

to develop an immunogenetic signature of Notch 

signaling components, their receptors, ligands and 

downstream targets, in various racial/ethnic 

populations and establish their association with 

antitumor immune response patterns impacting 

cancer etiology. The studies could also shed light on 

the prognostic aspects of Notch in predicting 

possible cancer health disparities and the outcome 

of immunotherapy. Findings of these prospective 

studies would be critical to devise strategies to 

reverse Notch dysfunction in lymphocytes for 

effective tumor eradication and durable remission in 

cancer patients of varied ethnic backgrounds. 

Acknowledgements 

The authors are thankful to the editorial board of 

Cancer Health Disparities for inviting this article. 

They are also thankful to Gladys Simiyu, PhD and 

Siddharth Pratap, PhD for help with the TCGA data 

sets. 

Funding 

AS is supported by funds from the following National 

Institutes of Health (NIH) grants U54 CA163069-6963, 

U54 MD007593, SC1 CA182843, and R01 CA175370. 

PLT is an MD PhD candidate supported by grant 

S21MD000104. 

 



 
 
 
 
 

 

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Conflict of interest 
The authors declare that no competing or conflict of 

interests exist. The funders had no role in study 

design, writing of the manuscript, or decision to 

publish. 

Authors’ contributions 
Conception and design: AS 

Literature review and manuscript writing: PLT, AS 

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