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Strategies for Targeting Cancer Immunotherapy Through Modulation of the Tumor Microenvironment

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Abstract

Cancer immunotherapeutic strategies have shifted the focus of cancer treatment from eradicating the tumor cell by conventional cytotoxic chemotherapy, to educating the immune system to eliminate tumor, thereby preventing the recurrence of cancer. The understanding of tumor microenvironment and its components which generate an immunosuppressive environment is critical in further develo** efficient immunotherapies. In this review, we have classified the current immunotherapies based on their effect in modulating the tumor microenvironment. Additionally, we propose the inclusion of nanotechnology and tissue engineering approaches, which provide unique strategies to enhance the therapeutic efficacy and could lead to develo** nano/engineered immunotherapies for improved clinical outcomes. Specifically, we focus on criteria for designing nano/engineered immunotherapies and discuss targeted delivery strategies that can optimize the bioavailability of immunotherapies and, in turn, improve the therapeutic outcomes in the treatment of cancer.

Lay Summary

Several strategies aimed to exploit the therapeutic benefits of immunotherapy are based on alterations of the complex immunosuppressive tumor microenvironment. Such targeted approaches have also been significantly improved by various design criteria based on the concepts of nanotechnology and tissue engineering. The properties of specific targeting, controlled release, and ability to attain enhanced therapeutic effects with low doses conferred by these approaches have immensely helped to surmount the side effects and off-target issues of existing methods. Incorporation of these design criteria while develo** various carrier systems for targeted immunotherapy would certainly enhance their clinical translation potential, eventually augmenting anti-tumor responses.

Future Work

Modulation of tumor microenvironment with strategies discussed in this review will provide additional opportunities to improve cancer immunotherapy, especially in challenging diseases such as pancreatic and brain tumors. Various design attributes with targeted systems would provide numerous advantages, widening the scope of clinical translation and benefits to cancer patients.

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Abbreviations

TME:

tumor microenvironment

CAF:

cancer-associated fibroblasts

Tregs :

regulatory T cells

MDSC:

myeloid-derived suppressor cells

TAM:

tumor-associated macrophages

DCs:

dendritic cells

FAPa:

fibroblast activation protein

TCR:

T cell receptor

CAR:

chimeric antigen receptor

CAR-T:

CAR-expressing T cells

DAMP:

damage-associated molecular patterns

CpG-ODNs:

Cytosine-guanosine oligodeoxynucleotide

GPI:

glycosyl-phosphatidylinositol

pal-prot A:

palmitated protein A

HER2:

human epidermal growth factor receptor 2

ADCC:

antibody-dependent cell-mediated cytotoxicity

TDLN:

tumor-draining lymph nodes

APC:

antigen presenting cells

PPS:

poly(propylene) sulfide

TLR:

toll-like receptor

TRP2:

tyrosine-related protein 2

TADCs:

tumor-associated dendritic cells

SLBs:

supported lipid bilayers

MSRs:

mesoporous silica microrods

APC-ms:

APC-mimetic scaffolds

MSNP:

mesoporous silica nanoparticles

CRS:

cytokine-release syndrome

ROS:

reactive oxygen species

GEM:

gemcitabine

GM-CSF:

granulocyte-macrophage colony stimulating factor

HA:

hyaluronic acid

PEI:

poly(ethyleneimine)

NSCLC:

non-small cell lung cancer

GAC:

gastric adenocarcinoma

IFP:

interstitial fluid pressure

IDO1:

indoleamine 2,3-dioxygenase-1

ALL:

acute lymphoblastic leukemia

NK:

natural killer cells

TILs:

tumor infiltrating lymphocytes

PEGPH20:

PEGylated recombinant human hyaluronidase PH20

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Acknowledgments

SP acknowledges Department of Science & Technology DST-INSPIRE, Government of India for her Senior Research Fellowship and the additional funding from Department of Biotechnology, Government of India through Pilot Project Grants, Program for Young Investigators in Cancer Biology. She also acknowledges Amrita Vishwa Vidyapeetham for PhD Scholar’s Fellowship (2017) and the infrastructural support.

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  1. Neha Parayath

    Present address: Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, 98109, USA

  2. Neha Parayath and Smrithi Padmakumar contributed equally to this work.

Authors and Affiliations

  1. Department of Pharmaceutical Sciences, School of Pharmacy, Northeastern University, Boston, MA, 02115, USA

    Neha Parayath, Smrithi Padmakumar & Mansoor M. Amiji

  2. Centre for Nanosciences and Molecular Medicine, Amrita Institute of Medical Sciences, Amrita Vishwa Vidyapeetham, Kochi, Kerala, India

    Smrithi Padmakumar, Shantikumar V. Nair & Deepthy Menon

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Parayath, N., Padmakumar, S., Nair, S.V. et al. Strategies for Targeting Cancer Immunotherapy Through Modulation of the Tumor Microenvironment. Regen. Eng. Transl. Med. 6, 29–49 (2020). https://doi.org/10.1007/s40883-019-00113-6

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