Добавил:
Sekretar
kiopkiopkiop18@yandex.ru
t.me/Prokururor I Вовсе не секретарь, но почту проверяю
Опубликованный материал нарушает ваши авторские права? Сообщите нам.
Вуз:
Предмет:
Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5563_Библиотеки_им_академика_М_И_Перельмана.pdf
86 The Dynamics of Tumor Microenvironment and Therapeutic Targets
4.7 ROLE OF TUMOR ENDOTHELIAL CELLS IN ANGIOGENESIS
ECs have angiogenic potential, the process of formation of new blood vessels by ECs
during development, reproduction, wound healing in normal physiological condi-
tion. Under normal conditions, this process is tightly regulated and balanced by pro-
and anti-angiogenic factors, where pro-angiogenic factors promote angiogenesis and
anti-angiogenic factors inhibit the process. For example, some of the pro-angiogenic
factors include broblast growth factor (FGF), vascular endothelial growth factor
(VEGF), platelet-derived endothelial cell growth factor, angiogenin, transforming
growth factor-β (TGF-β), insulin-like growth factor (IGF), angiopoietins, adhesion
molecules, and matrix metalloproteinases (MMPs). Similarly, few of anti-angiogenic
factors include endostatin, angiostatin, thrombospondin, tumstatin, interferon, plate-
let factor 4, vasohibin, interleukin, chondromodulin, chemokines, pigment epithelial-
derived factor, isthmin1 (ISM1), carboxy-terminus of Hsc70 interacting protein
(CHIP), multimerin-2, and G-protein coupled receptor 56 (GPR56) (Folkman and
Shing, 1992; Liu et al., 2023; Huang and Bao, 2004).
Tumors require blood supply to ll their necessity for oxygen and nutrients and
to achieve other metabolic functions. Multiple signaling pathways such as VEGF-
VEGFR, FGF, notch, angiopoietin-tie, platelet-derived growth factor (PDGF), trans-
forming growth factor-beta (TGF-β), Ephrin-Eph are involved in angiogenesis process.
The chief driver of tumor-induced angiogenesis is hypoxia. Hypoxic cancer cells
secrete vascular endothelial growth factor A(VEGFA), which initiates tumor angio-
genesis by appointing VEGF receptor 2 (VEGFR2) expressed on the ECs of neigh-
boring blood vessels. Adverse hypoxic conditions within tumors stimulate the VEGF/
VEGFR axis, which, in turn, activates signaling pathways for neovascularization. This
process is regulated at multiple levels. Neovascularization/angiogenesis serves the pur-
pose and is the process of development of new blood vessels from a pre-existing vascu-
lar network. Gradients of soluble VEGFA induce the formation of motile ECs, called
tip cells, which split the surrounding ECM and promote the growth of new vascular
sprouts toward VEGFA. This process also requires involvement of other signaling mol-
ecules, including delta ligand-like 4 (DLL4) and angiopoietin 2 (ANGPT2), which,
respectively, control the tip-cell phenotype and destabilize EC junctions. Every layer of
the tumor vessels lined by the ECs has disordered organization and exhibit abnormal
structure and function. The ECs lack a cobblestone appearance, are poorly intercon-
nected, and are occasionally multilayered (Potente et al., 2011; De Palma et al., 2017).
In contrast the angiogenic inhibitor like thrombospondin also binds to the transmem-
brane receptors expressed by the ECs, to counterforce angiogenesis.
4.8 ENDOTHELIAL CELLS IN CANCER THERAPY
The TECs lining the inner layer of blood vessels of the tumor stromal tissue are the
key targets of anti-angiogenic therapy. Dr. Folkman proposed this concept of target-
ing the TECs with angiogenic inhibitors as an important strategy for cancer treatment
(Folkman, 2007; Hida et al., 2016). Several emerging therapeutic approaches have
aimed to combine anti-angiogenic treatments with immunotherapy strategies to simul-
taneously target ECs and immune cells, potentially enhancing antitumor responses.
87Endothelial Cells in Tumor Microenvironment
TECs in the tumor vasculature show high glycolytic cellular morphology and
have higher glycolytic ux to generate ATP compared to normal ECs (Rohlenova
et al., 2020; Zecchin et al., 2017). They show an enhanced expression of the GLUT1
glucose transporter and the PFKFB3 glycolytic activator, which alters expression of
glycolytic enzymes and also enhances secretion of pro-angiogenic growth factors
like VEGF (Yeh et al., 2008; Cantelmo et al., 2016). Therapeutic targets that inhibit
PFKFB3 function can inhibit proliferation of these TECs and regularize the tumor
vasculature. The aim is to decrease the level of glycolysis, inhibit metastasis, and
prevent aggressive cancer (Conradi et al., 2017; Xu et al., 2024).
The normal ECs show an enhanced expression of adhesion molecules like
ICAM-1, VCAM-1 and E-selectin in response to tumor necrosis factor (TNFα), inter-
feron γ (IFNγ), and interleukin-1. In contrast, the angiogenic TECs are anergic to
such signaling, leading to lesser inltration of immune cell into tumors (Grifoen
et al., 1996). EC anergy is a governing function of angiogenesis whereby the cancer
cells to restrain immune surveillance (Huijbers et al., 2022).
This phenomenon of angiogenesis-induced immune suppression signies a vas-
cular immune checkpoint, which piloted the hypothesis of inhibiting angiogenesis
to induce pro-inammatory activities (van Beijnum et al., 2022) and has been used
in combinatorial immunotherapy and anti-angiogenic therapy. Immune checkpoint
inhibition is signicantly enhanced by treatment with angiogenesis inhibitors, mainly
those targeting the VEGF signaling pathway (Ramjiawan et al., 2017; Dudley and
Grifoen, 2023).
4.9 DISCUSSION
Endothelial cells (ECs) in the tumor microenvironment (TME) often exhibit abnor-
mal characteristics, including a high proliferative potential and the ability to activate
immunosuppressive mechanisms. As integral components of the TME and gatekeep-
ers for tumor-inltrating immune cells, ECs play a critical role in supporting cancer
growth, immune evasion, and treatment resistance. Characterizing the phenotypic
and functional differences between normal endothelial cells and tumor endothe-
lial cells (TECs) may help identify specic drug targets to improve cancer therapy.
Targeting TECs in cancer immunotherapy has shown promising results, albeit with
some exceptions. Tumor progression by ECs are distinct and critically regulated by
other components in the TME. These functions can be categorized as angiogenesis,
modulation of vascular permeability, recruitment of immune cells, remodeling of
extracellular matrix, to conditions like hypoxia and nutrient deciency have been
discussed vividly. Understanding EC biology, both in normal and tumor-associated
states, could pave the way for novel cancer treatment strategies.
TECs are responsible for angiogenesis and facilitate cancer cell migration, inva-
sion, and metastasis. Furthermore, they can inuence the effectiveness of immune
checkpoint inhibitors and contribute to the formation of tertiary lymphoid structures,
which may enhance responses to immunotherapy. Adeeper understanding of TECs,
along with their normal counterparts, could help establish unconventional and more
effective treatment regimens for cancer.
88 The Dynamics of Tumor Microenvironment and Therapeutic Targets
REFERENCES
Aird WC. Endothelial cell heterogeneity. Cold Spring Harb Perspect Med. 2012 Jan;
2(1):a006429. https://doi.org/10.1101/cshperspect.a006429. PMID: 22315715; PMCID:
PMC3253027.
Amersfoort J, Eelen G, Carmeliet P. Immunomodulation by endothelial cells—partnering up with
the immune system? Nat Rev Immunol. 2022 Sep;22(9):576–588. https://doi.org/10.1038/
s41577-022-00694-4. Epub 2022 Mar 14. PMID: 35288707; PMCID: PMC8920067.
Amin DN, Hida K, Bielenberg DR, Klagsbrun M. Tumor endothelial cells express epider-
mal growth factor receptor (EGFR) but not ErbB3 and are responsive to EGF and to
EGFR kinase inhibitors. Cancer Res. 2006 Feb 15;66(4):2173–2180. https://doi.
org/10.1158/0008-5472.CAN-05-3387. PMID: 16489018.
Braun A, Anders HJ, Gudermann T, Mammadova-Bach E. Platelet-cancer interplay: Molecular
mechanisms and new therapeutic avenues. Front Oncol. 2021 Jul 12;11:665534. https://
doi.org/10.3389/fonc.2021.665534. PMID: 34322381; PMCID: PMC8311658.
Cantelmo AR, Conradi LC, Brajic A, Goveia J, Kalucka J, Pircher A, Chaturvedi P, Hol J,
Thienpont B, Teuwen LA, Schoors S, Boeckx B, Vriens J, Kuchnio A, Veys K, Cruys B,
Finotto L, Treps L, Stav-Noraas TE, Bifari F, Stapor P, Decimo I, Kampen K, De Bock K,
Haraldsen G, Schoonjans L, Rabelink T, Eelen G, Ghesquière B, Rehman J, Lambrechts
D, Malik AB, Dewerchin M, Carmeliet P. Inhibition of the glycolytic activator PFKFB3
in endothelium induces tumor vessel normalization, impairs metastasis, and improves
chemotherapy. Cancer Cell. 2016 Dec 12;30(6):968–985. https://doi.org/10.1016/j.
ccell.2016.10.006. Epub 2016 Nov 17. PMID: 27866851; PMCID: PMC5675554.
Carman CV, Martinelli R. T lymphocyte-endothelial interactions: Emerging understanding of
trafcking and antigen-specic immunity. Front Immunol. 2015 Nov 24;6:603. https://
doi.org/10.3389/mmu.2015.00603. PMID: 26635815; PMCID: PMC4657048.
Conradi LC, Brajic A, Cantelmo AR, Bouché A, Kalucka J, Pircher A, Brüning U, Teuwen LA,
Vinckier S, Ghesquière B, Dewerchin M, Carmeliet P. Tumor vessel disintegration by
maximum tolerable PFKFB3 blockade. Angiogenesis. 2017 Nov;20(4):599–613. https://
doi.org/10.1007/s10456-017-9573-6. Epub 2017 Sep 5. PMID: 28875379.
De Palma M, Biziato D, Petrova TV. Microenvironmental regulation of tumour angiogenesis.
Nat Rev Cancer. 2017 Aug;17(8):457–474. https://doi.org/10.1038/nrc.2017.51. Epub
2017 Jul 14. PMID: 28706266.
De Val S, Black BL. Transcriptional control of endothelial cell development. Dev Cell.
2009;16(2):180–195.
Dudley AC, Grifoen AW. Pathological angiogenesis: Mechanisms and therapeutic strategies.
Angiogenesis. 2023 Aug;26(3):313–347. https://doi.org/10.1007/s10456-023-09876-7.
Epub 2023 Apr 15. PMID: 37060495; PMCID: PMC10105163.
Folkman J. Angiogenesis: An organizing principle for drug discovery? Nat Rev Drug Discov.
2007 Apr;6(4):273–286. https://doi.org/10.1038/nrd2115. PMID: 17396134.
Folkman J, Shing Y. Angiogenesis. J Biol Chem. 1992;267(16):10931–10934.
Galley HF, Webster NR. Physiology of the endothelium. Br J Anaesth. 2004;93(1):105–113.
Gao D, Nolan D, McDonnell K, Vahdat L, Benezra R, Altorki N, Mittal V. Bone marrow-
derived endothelial progenitor cells contribute to the angiogenic switch in tumor growth
and metastatic progression. Biochim Biophys Acta. 2009 Aug;1796(1):33–40. https://
doi.org/10.1016/j.bbcan.2009.05.001. Epub 2009 May 19. PMID: 19460418; PMCID:
PMC3649840.
Geldhof V, de Rooij LPMH, Sokol L, Amersfoort J, De Schepper M, Rohlenova K, Hoste
G, Vanderstichele A, Delsupehe AM, Isnaldi E, Dai N, Taverna F, Khan S, Truong
AK, Teuwen LA, Richard F, Treps L, Smeets A, Nevelsteen I, Weynand B, Vinckier
S, Schoonjans L, Kalucka J, Desmedt C, Neven P, Mazzone M, Floris G, Punie K,
89Endothelial Cells in Tumor Microenvironment
Dewerchin M, Eelen G, Wildiers H, Li X, Luo Y, Carmeliet P. Single cell atlas identi-
es lipid-processing and immunomodulatory endothelial cells in healthy and malignant
breast. Nat Commun. 2022 Sep 20;13(1):5511. https://doi.org/10.1038/s41467-022-
33052-y. PMID: 36127427; PMCID: PMC9489707.
Grifoen AW, Damen CA, Blijham GH, Groenewegen G. Tumor angiogenesis is accompanied
by a decreased inammatory response of tumor-associated endothelium. Blood. 1996
Jul 15;88(2):667–673. PMID: 8695814.
Hida K, Maishi N, Torii C, Hida Y. Tumor angiogenesis—characteristics of tumor endothelial
cells. Int J Clin Oncol. 2016 Apr;21(2):206–212. https://doi.org/10.1007/s10147-016-
0957-1. Epub 2016 Feb 15. PMID: 26879652.
Hinshaw DC, Shevde LA. The tumor microenvironment innately modulates cancer progres-
sion. Cancer Res. 2019 Sep 15;79(18):4557–4566. https://doi.org/10.1158/0008-5472.
CAN-18-3962. Epub 2019 Jul 26. PMID: 31350295; PMCID: PMC6744958.
Huang Z, Bao SD. Roles of main pro- and anti-angiogenic factors in tumor angiogenesis.
World J Gastroenterol. 2004;10(4):463–470.
Huijbers EJM, Khan KA, Kerbel RS, Grifoen AW. Tumors resurrect an embryonic vascular
program to escape immunity. Sci Immunol. 2022 Jan 14;7(67):eabm6388. https://doi.
org/10.1126/sciimmunol.abm6388. Epub 2022 Jan 14. PMID: 35030032.
Kim YW, Byzova TV. Oxidative stress in angiogenesis and vascular disease. Blood. 2014 Jan
30;123(5):625–631. https://doi.org/10.1182/blood-2013-09-512749. Epub 2013 Dec 3.
PMID: 24300855; PMCID: PMC3907751.
Klein D. The tumor vascular endothelium as decision maker in cancer therapy. Front Oncol.
2018 Sep 10;8:367. https://doi.org/10.3389/fonc.2018.00367. PMID: 30250827; PMCID:
PMC6139307.
Lambrechts D, Wauters E, Boeckx B, Aibar S, Nittner D, Burton O, Bassez A, Decaluwé
H, Pircher A, Van den Eynde K, Weynand B, Verbeken E, De Leyn P, Liston A,
Vansteenkiste J, Carmeliet P, Aerts S, Thienpont B. Phenotype molding of stromal cells
in the lung tumor microenvironment. Nat Med. 2018 Aug;24(8):1277–1289. https://doi.
org/10.1038/s41591-018-0096-5. Epub 2018 Jul 9. PMID: 29988129.
Liu S, Qin T, Liu Z, Wang J, Jia Y, Feng Y, Gao Y, Li K. Anlotinib alters tumor immune micro-
environment by downregulating PD-L1 expression on vascular endothelial cells. Cell
Death Dis. 2020 May 4;11(5):309. https://doi.org/10.1038/s41419-020-2511-3. PMID:
32366856; PMCID: PMC7198575.
Liu ZL, et al. Angiogenic signaling pathways and anti-angiogenic therapy for cancer. Signal
Transduct Target Ther. 2023;8(1):198.
Mai J, et al. An evolving new paradigm: Endothelial cells—conditional innate immune cells.
J Hematol Oncol. 2013;6:61.
Potente M, Carmeliet P. The link between angiogenesis and endothelial metabolism. Annu
Rev Physiol. 2017 Feb 10;79:43–66. https://doi.org/10.1146/annurev-physiol-021115-
105134. Epub 2016 Dec 15. PMID: 27992732.
Potente M, Gerhardt H, Carmeliet P. Basic and therapeutic aspects of angiogenesis. Cell. 2011
Sep 16;146(6):873–887. https://doi.org/10.1016/j.cell.2011.08.039. PMID: 21925313.
Ramjiawan RR, Grifoen AW, Duda DG. Anti-angiogenesis for cancer revisited: Is there a role
for combinations with immunotherapy? Angiogenesis. 2017 May;20(2):185–204. https://
doi.org/10.1007/s10456-017-9552-y. Epub 2017 Mar 30. PMID: 28361267; PMCID:
PMC5439974.
Reiterer M, Branco CM. Endothelial cells and organ function: Applications and implications
of understanding unique and reciprocal remodelling. FEBS J. 2020;287(6):1088–1100.
Rohlenova K, Goveia J, García-Caballero M, Subramanian A, Kalucka J, Treps L, Falkenberg
KD, de Rooij LPMH, Zheng Y, Lin L, Sokol L, Teuwen LA, Geldhof V, Taverna F,
Pircher A, Conradi LC, Khan S, Stegen S, Panovska D, De Smet F, Staal FJT, Mclaughlin
90 The Dynamics of Tumor Microenvironment and Therapeutic Targets
RJ, Vinckier S, Van Bergen T, Ectors N, De Haes P, Wang J, Bolund L, Schoonjans L,
Karakach TK, Yang H, Carmeliet G, Liu Y, Thienpont B, Dewerchin M, Eelen G, Li X,
Luo Y, Carmeliet P. Single-cell RNA sequencing maps endothelial metabolic plasticity
in pathological angiogenesis. Cell Metab. 2020 Apr 7;31(4):862–877.e14. https://doi.
org/10.1016/j.cmet.2020.03.009. PMID: 32268117.
Sato Y. Persistent vascular normalization as an alternative goal of anti-angiogenic cancer
therapy. Cancer Sci. 2011 Jul;102(7):1253–1256. https://doi.org/10.1111/j.1349-
7006.2011.01929.x. Epub 2011 Apr 14. PMID: 21401807.
Sturtzel C. Endothelial cells. Adv Exp Med Biol. 2017;1003:71–91. https://doi.org/10.1007/
978-3-319-57613-8_4. PMID: 28667554.
van Beijnum JR, Huijbers EJM, van Loon K, Blanas A, Akbari P, Roos A, Wong TJ, Denisov
SS, Hackeng TM, Jimenez CR, Nowak-Sliwinska P, Grifoen AW. Extracellular vimen-
tin mimics VEGF and is a target for anti-angiogenic immunotherapy. Nat Commun. 2022
May 23;13(1):2842. https://doi.org/10.1038/s41467-022-30063-7. PMID: 35606362;
PMCID: PMC9126915.
Xiao Y, Yu D. Tumor microenvironment as a therapeutic target in cancer. Pharmacol Ther.
2021 May;221:107753. https://doi.org/10.1016/j.pharmthera.2020.107753. Epub 2020
Nov 28. PMID: 33259885; PMCID: PMC8084948.
Xu S, Liao J, Liu B, Zhang C, Xu X. Aerobic glycolysis of vascular endothelial cells:
Anovel perspective in cancer therapy. Mol Biol Rep. 2024 Jun 1;51(1):717. https://doi.
org/10.1007/s11033-024-09588-1. PMID: 38824197; PMCID: PMC11144152.
Yeh WL, Lin CJ, Fu WM. Enhancement of glucose transporter expression of brain endothelial
cells by vascular endothelial growth factor derived from glioma exposed to hypoxia. Mol
Pharmacol. 2008 Jan;73(1):170–177. https://doi.org/10.1124/mol.107.038851. Epub
2007 Oct 17. PMID: 17942749.
Young MD, Mitchell TJ, Vieira Braga FA, Tran MGB, Stewart BJ, Ferdinand JR, Collord
G, Botting RA, Popescu DM, Loudon KW, Vento-Tormo R, Stephenson E, Cagan A,
Farndon SJ, Del Castillo Velasco-Herrera M, Guzzo C, Richoz N, Mamanova L, Aho
T, Armitage JN, Riddick ACP, Mushtaq I, Farrell S, Rampling D, Nicholson J, Filby A,
Burge J, Lisgo S, Maxwell PH, Lindsay S, Warren AY, Stewart GD, Sebire N, Coleman
N, Haniffa M, Teichmann SA, Clatworthy M, Behjati S. Single-cell transcriptomes
from human kidneys reveal the cellular identity of renal tumors. Science. 2018 Aug
10;361(6402):594–599. https://doi.org/10.1126/science.aat1699. PMID: 30093597;
PMCID: PMC6104812.
Yu X, Chen L, Liu J, Dai B, Xu G, Shen G, Luo Q, Zhang Z. Immune modulation of liver
sinusoidal endothelial cells by melittin nanoparticles suppresses liver metastasis. Nat
Commun. 2019 Feb 4;10(1):574. https://doi.org/10.1038/s41467-019-08538-x. PMID:
30718511; PMCID: PMC6361944.
Zecchin A, Kalucka J, Dubois C, Carmeliet P. How endothelial cells adapt their metabolism
to form vessels in tumors. Front Immunol. 2017 Dec 11;8:1750. https://doi.org/10.3389/
mmu.2017.01750. PMID: 29321777; PMCID: PMC5732229.
91
5
Therapeutic Interventions
in Modulating Tumor
Microenvironment
Debasis Bisoi and Lopamudra Das
5.1 INTRODUCTION
Cancer or tumor is a disease dened and driven by genomic instability, chromosomal
alterations, and genetic mutations. Traditional treatment strategies for cancer include
chemotherapy, surgery, radiotherapy, and immunotherapy. In recent years due to
the recognition of critical roles played by the tumor microenvironment (TME) in
regulating tumor progression and modulating response to standard-of-care therapies,
strategies to therapeutically target the TME are explored as a promising approach for
cancer treatment.
The formation and progression of tumor is inuenced genetic/epigenetic changes
in the tumor cells and the rearrangement of the components of the TME through
mutual and dynamic crosstalk. The TME typically comprises immune cells, includ-
ing T and B lymphocytes, tumor-associated macrophages, (TAM), antigen-presenting
cells (APC) including dendritic cells (DC), natural killer (NK) cells, neutrophils, and
myeloid-derived suppressor cells (MDSC); stromal cells, such as cancer-associated
broblasts (CAF), pericytes, and mesenchymal stromal cells; the extracellular matrix
(ECM) and other secreted molecules, such as growth factors, cytokines, chemokines,
and extracellular vesicles (EV); and the blood and lymphatic vascular networks.
There is a complex interplay of malignant cells, immune components, blood vessels,
extracellular matrix and signaling molecules in the TME (Junttila and de Sauvage
2013). The TME is characterized by areas of poor vascular perfusion, low pH, low
oxygen and nutrient levels, which attenuate the delivery and activity of cytotoxic
therapies by providing cytoprotective niches.
Depending on organ in which the tumor arises, the stage of cancer progression,
the cells in the TME can be either tumor-suppressive or tumor-supporting (Salmon
et al. 2019). There is a complex interaction between the cancer cells and the TME
which depends on the cancer type, the ontogeny of TME cells, and their “education”
within the tumor mass and/or at the systemic level. So one of the strategies include
depletion of cancer-promoting cells in the microenvironment or their “re-education”
to increase immune stimulating, tumor-suppressive phenotypes.
The TME also has a role in regulating the response to therapeutic intervention like
intrinsic resistance, existing prior to treatment, or as acquired/adaptive resistance
DOI: 10.1201/9781003405023-5
92 The Dynamics of Tumor Microenvironment and Therapeutic Targets
(Binnewies et al. 2018; Klemm and Joyce 2015). The intrinsic properties of the
TME, like elevated interstitial uid pressure (IFP) and an inefcient vascular sup-
ply, attenuate delivery and distribution of drugs within the tumor mass (5). Intrinsic
resistance to therapy can be attributed to high numbers of immunosuppressive cells,
including TAMs and regulatory T cells (Treg), and the presence of cytoprotective
niches (Sharma et al. 2017). So therapeutic strategies are employed which include
accumulation of immune cells elevations in chemokine production.
Both radiotherapy and chemotherapies may induce recurrence by increasing the
presence of immunosuppressive TAMs in tumors, protecting the cancer cells from
therapy induced cell death (Seifert et al. 2016; Takeuchi et al. 2015). Chemotherapy
by inducing DNA damage in stromal cells result in the activation of NFκB and upreg-
ulation of the WNT pathway can contribute to therapeutic resistance. Radiotherapy
alters tumor vasculature, resulting in hypoxia and the subsequent activation of hypoxia-
inducible factor 1 (HIF1), which promotes cancer cell survival and resistance to radio-
therapy. Radiotherapy can also activate CAFs in the TME, leading to radiation-induced
brosis, secretion of lysyl oxidase (LOX) enzymes that favor collagen deposition, and
elevated ECM production, which promotes cancer cell survival via integrin signaling.
Nevertheless certain therapies also induce changes in the TME that can have
a synergistic effect by promoting immunogenic cell death and enhancing T cell–
dependent antitumor immunity (Gupta et al. 2012; Vincent et al. 2010). These
approaches mainly focus on the targeting of TAMs, DCs, T cells, tumor vasculature,
ECM, and CAFs. Taking into cognizance of the various components and properties
of TME, multiple strategies are employed for therapeutic response. This chapter will
focus on therapies that either are in clinical evaluation or have been approved.
5.2 TME THERAPIES
The therapeutic strategies employed to modulate the TME can be broadly classied
as (1) therapies targeting the tumor-associated immune cells, (2) tumor vasculature,
(3) tumor-associated stroma and the extracellular matrix.
5.2.1 tumor-assoCiated immuNe Cells
5.2.1.1 Tumor-Associated Macrophages (TAMs)
The TME contains both resident macrophages and monocyte-derived macrophages
(MDM). They are further educated or modied within the TME producing phe-
notypic and functional heterogeneity as seen in cancers of brain, breast, pancreas,
and lung (Cassetta et al. 2019). Increased TAM population is often associated with
poor prognosis and therapeutic resistance. TAMs can promote tumor initiation by
inammation, subsequent tumor growth, and metastasis by enabling immune eva-
sion, angiogenesis, cancer cell invasion, and immunosuppression (Cassetta and
Pollard 2018). TAMs may cause increased of colony-stimulating factor 1 (CSF1) pro-
duction resulting enhanced MDM migration to the residual tumor (Xu et al. 2013).
Macrophage-targeted therapies block the ability of TAMs to directly promote cancer
cell survival and also increase cross-presentation to CD8+ T cells. Various targets
93Therapeutic Interventions in Modulating Tumor Microenvironment
have been identied and following strategies are being evaluated, which include
(i) CSF1 receptor (CSF1R) inhibitors to deplete TAMs and/or alter their functions
within the TME, (ii) CC-motif chemokine ligand 2 (CCL2) or CC-chemokine recep-
tor 2 (CCR2) inhibitors to prevent TAM recruitment into the TME, (iii) CD47/SIRPα
complex antagonists to enhance TAM-mediated phagocytosis of cancer cells, (iv)
costimulatory molecules such as CD40 to enhance T cell activation, and (v) PI3Kγ
and the triggering receptor expressed on myeloid cells 2 (TREM2) inhibitors.
5.2.1.1.1 Colony Stimulating Factor 1 Receptor (CSF1R) Inhibitors
CSF1R is a transmembrane tyrosine kinase class III receptor binds to its ligands,
CSF1 and IL34, in specic tissues, such as the brain, skin, liver, ovary, and endome-
trium (Lampiasi 2024). Increased CSF1R correlates with poor prognosis in tumors
of these organs. In preclinical tumor models of primary tumors of pancreas, breast,
glioblastoma neutralizing antibodies and small-molecule inhibitors directed against
CSF1R have been observed to reduce intratumoral TAMs or re-educate into a protu-
moricidal phenotype and reduce breast-to-lung metastasis (DeNardo et al. 2011). In
breast cancer preclinical models, the efcacy of paclitaxel was improved by CSF1R-
inhibitor-mediated TAM depletion (DeNardo et al. 2011). Similarly in preclinical
glioblastoma models CSF1R inhibition by TAM re-education increased the effec-
tiveness of radiotherapy and tyrosine kinase inhibitors (Yan et al. 2017).
Multiple drugs blocking CSF1R signaling (emactuzumab, ARRY-382, pexi-
dartinib, PLX7486, and BLZ945) have been evaluated with conventional thera-
pies in clinical trials. Emactuzumab has been evaluated in phase I and II trials in
patients with advanced-stage solid tumors (NCT02323191 and NCT02923739),
and ARRY-382 in patients with advanced solid tumors and metastatic disease
(NCT01316822). Evaluation of pexidartinib (PLX3397) monotherapy in a phase II
study (NCT01349036) for patients with recurrent glioblastoma showed good drug
tolerance and penetration of the blood–tumor barrier. Although pexidartinib was
seen to deplete TAMs in patient tumor biopsies, clinical improvement like progres-
sion-free survival (PFS) was not improved, and no partial responses (PR) or complete
responses (CR) were observed (Butowski et al. 2016). But pexidartinib, in a phase
III study of patients with advanced tenosynovial giant cell tumor (TGCT), showed
robust tumor regression and improvement of symptoms in and was approved by the
FDA as an oral medication for TGCT (Tap et al. 2019). The resistance to CSF1R
inhibitors may be due to activation of compensatory IL4/IGF1R/PI3K signaling in
the TME leading to recurrence or expression of CSF1R in other cells like MDSCs,
cancer cells, and even neurons, the ontogeny and functional TAM heterogeneity
observed in different TMEs (Luo et al. 2013). Hence, new strategies need to be devel-
oped by deciphering the proles and phenotypes of the diverse TAM populations to
target the tumor-promoting functions of TAMs.
5.2.1.1.2 C-C Motif Chemokine Ligand 2 and C-C Chemokine
Receptor 2 (CCL2/CCR2) Inhibitors
Tumor cells release chemokines which leads to monocyte recruitment and MDM
accumulation within the tumor and also the expansion of the tissue-resident macro-
phage pool. CCL2 recruits both tissue-resident macrophages and CCR2-expressing
94 The Dynamics of Tumor Microenvironment and Therapeutic Targets
Ly6Chi monocytes and differentiate into TAMs. High CCL2 levels in the serum
and the TME are poor prognostic factors in cancers of breast and prostate (Lebrecht
et al. 2004; Loberg et al. 2007). Carlumab/CNTO888 (targeting CCL2) was evalu-
ated in phase I and II trials for patients with metastatic castrate-resistant prostate
cancer (NCT00992186 and NCT01204996). Though well tolerated, it failed to pro-
duce signicant clinical benet and the drug was discontinued.
PF-04136309 (anti-CCR2 mAbs), together with FOLFIRINOX chemotherapy
(folinic acid, uorouracil, irinotecan, and oxaliplatin), showed good tumor response
in 49% of the patients of advanced pancreatic adenocarcinoma and local tumor con-
trol in 96% but not when PF-04136309 was used alone (Nywening et al. 2016). This
may be explained by compensatory mechanisms in the CCL2/CCR2 axis, angiogen-
esis, and local proliferation of resident TAMs.
5.2.1.1.3 CD47 Antagonists
CD47 is an anti-phagocytosis immune checkpoint signaling receptor, constitutively
expressed by normal cells and overexpressed on cancer cells. CD47 binds to the signal
regulatory protein α (SIRPα) and initiates a signaling cascade that inhibits the phago-
cytic capacity of macrophages. So blocking CD47–SIRPα interactions increases the
macrophage-mediated clearance of cancer cells (Matlung et al. 2017). CD47 inhibition
also induces DC endocytosis and activation, increasing T-cell-mediated tumor clearance
(Edris et al. 2012). Magrolimab an anti-CD47 antibody showed good results in mouse
pediatric brain tumors (Gholamin et al. 2017). Other anti-CD47 mAbs (Hu5F9-G4,
CC-90002, and ZL-1201) and recombinant SIRPα-crystallizable fragment fusion pro-
teins (TTI-621 and TTI-622 are being evaluated in both solid tumors and hematologic
and B cell malignancies (NCT03558139, NCT03248479, and NCT04599634). The
results of a phase II trial using magrolimab with cetuximab (NCT02953782) for the
treatment of solid tumors and advanced colorectal cancer are encouraging.
5.2.1.1.4 CD40 Agonists
CD40 is a cell-surface receptor a TNF receptor super-family member expressed on
APCs (including TAMs and DCs) and is critical for their activation and proliferation.
The interaction of CD40 with CD40 ligand (CD40L), mainly expressed by CD4+ T cells
results in the upregulation of MHC molecules and production of pro-inammatory cyto-
kines (e.g., IL12), which are crucial for T cell priming. In DCs, CD40 activation leads
to an increase in costimulatory molecules (CD80 and CD86), production of cytokines,
enhanced expression of MHC molecules, and survival factors. In preclinical models
of pancreatic cancer and in patients with cancer, tumor regression has been seen with
agonist antibodies to CD40 (Beatty et al. 2011). This TAM reprogramming was more
pronounced when agonist antibodies to CD40 was in was used in combination with
CSF1R inhibition (Hoves et al. 2018). Several trials are evaluating CD40 monoclonal
agonistic antibodies (e.g., rhuCD40L, CP-870, 893, and RO7009789) for solid tumors.
5.2.1.1.5 Emerging TAM Targets
PI3K and TREM2 inhibition are new targets under evaluation. The PI3K signaling
pathway plays important role in regulating cell growth, motility, cell survival, metab-
olism, angiogenesis, and immune system. In mouse tumor models, PI3Kγ inhibition
95Therapeutic Interventions in Modulating Tumor Microenvironment
showed antitumoral activity and overcome resistance to ICI, reshaping the TME and
promote T cell mediated cancer suppression (Yang et al. 2019). PI3Kγ inhibitor egan-
elisib is now evaluated in phase Iand II clinical studies in diverse cancers, either as a
monotherapy or in combination with immune checkpoint inhibitors (NCT03719326,
NCT02637531, NCT03795610, and NCT03980041). TREM2 receptor, a member of
the Ig superfamily and a major signaling hub, interacts with the adaptor proteins
DNAX activation protein (DAP10 and DAP12), as well as numerous extracellular
ligands (Deczkowska, Weiner, and Amit 2020). In mice, deciency of TREM2 con-
verted TAMs from an immunosuppressive to an antitumoral phenotype. TREM2
deletion combined with PD-1 inhibition reduced tumor growth in several different
animal models (Molgora et al. 2020). Aphase Itrial is using PY314 (humanized
mAb to deplete TREM2-expressing TAMs) as a monotherapy or in combination with
pembrolizumab (NCT04691375)
5.2.1.2 Other Myeloid-Derived Cells, Including MDSCs and Neutrophils
Adaptive mechanisms of resistance to CSF1R inhibitors involving MDSCs have also
been reported. After CSF1R inhibition, CAFs can release granulocyte-recruiting
chemokines, leading to an increase in tumor-promoting MDSCs and cancer out-
growth in several mouse models. These adaptive effects could be reduced by the
addition of a CXCR2 inhibitor, and further enhanced in combination with anti-PD-1
treatment (Kumar et al. 2017). Neutrophils have been seen to have tumor protecting
functions in cancer metastasis. Several preclinical and clinical studies are evaluat-
ing different aspects of neutrophil biology including their recruitment, activation, or
functional response.
5.2.1.3 Dendritic Cells
Dendritic cells are APCs that take up, process, and present antigens to CTLs. DCs
present extracellular antigens on MHC-II molecules to CD4+ T cells and can also
cross present antigens on MHC-I molecules to CD8+ cytotoxic lymphocytes (CTL).
Optimal migratory capacity between lymphoid and nonlymphoid tissues, cross-
presentation of tumor-associated antigens (TAA) to CD8+ CTLs and chemokine and
cytokine release to modulate the overall immune response are needed for a robust
antitumor response (Perez and De Palma 2019). Different strategies are being evalu-
ated to manipulate DCs, including (i) administration of FLT3L to trigger expansion and
survival of the DC pool in vivo, (ii) modulation of DC activity through GM-CSF, and
(iii) creation of DC vaccines to boost antitumor immunity (Daud et al. 2008; Spitler
et al. 2009; Zhang et al. 2018).
5.2.1.3.1 FLT3 (FMS-Related Tyrosine Kinase 3)
FLT3 tyrosine kinase receptor binds with its ligand, FLT3L augments DC numbers
in the TME and provides a maturation stimulus to DCs, thus improving antitumor T
cell priming. Recombinant FLT3L (CDX-301) is being evaluated as single agent in
patients with acute myeloid leukemia, in a phase III trial (NCT00006223) and also
under clinical evaluation in patients with solid tumors (NCT00003431). FLT3L in
combination of radiotherapy with the costimulatory molecule CD40 is currently in
phase II trials in patients with lung cancer (NCT04491084).