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Frontiers of Medicine

ISSN 2095-0217

ISSN 2095-0225(Online)

CN 11-5983/R

Postal Subscription Code 80-967

2018 Impact Factor: 1.847

Front. Med.    2018, Vol. 12 Issue (4) : 426-439
Complex interplay between tumor microenvironment and cancer therapy
Minhong Shen, Yibin Kang()
Department of Molecular Biology, Princeton University, Princeton, NJ 08544, USA
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Tumor microenvironment (TME) is comprised of cellular and non-cellular components that exist within and around the tumor mass. The TME is highly dynamic and its importance in different stages of cancer progression has been well recognized. A growing body of evidence suggests that TME also plays pivotal roles in cancer treatment responses. TME is significantly remodeled upon cancer therapies, and such change either enhances the responses or induces drug resistance. Given the importance of TME in tumor progression and therapy resistance, strategies that remodel TME to improve therapeutic responses are under developing. In this review, we provide an overview of the essential components in TME and the remodeling of TME in response to anti-cancer treatments. We also summarize the strategies that aim to enhance therapeutic efficacy by modulating TME.

Keywords tumor microenvironment      therapy response      treatment resistance     
Corresponding Authors: Yibin Kang   
Just Accepted Date: 10 July 2018   Online First Date: 10 August 2018    Issue Date: 03 September 2018
 Cite this article:   
Minhong Shen,Yibin Kang. Complex interplay between tumor microenvironment and cancer therapy[J]. Front. Med., 2018, 12(4): 426-439.
Fig.1  TME components that regulate tumor progression. Schematic illustration of the major cellular and non-cellular components of TME that either promote (pink arrows) or inhibit (green “T” shapes) tumor progression. ECM, extracellular matrix; MDSC, myeloid derived suppressor cell; TAM, tumor-associated macrophage; Treg, regulatory T cell; CTL, cytotoxic T lymphocyte; NK, natural killer cell; CAF, cancer-associated fibroblast; TEC, tumor-associated endothelial cell; Th, CD4+ T helper lymphocyte; TIDC, tumor-infiltrating dendritic cell; TAN, tumor-associated neutrophil; TIL B, tumor-infiltrating lymphocyte B cell.
Fig.2  Treatment-induced TME remodeling that inhibits tumor progression or promotes treatment resistance. Top: treatment-induced TME remodeling with tumor inhibitory effect: chemo-/radio- and some target therapies could increase CTL and NK cell infiltration or activities, and decrease MDSC number in TME; targeted therapy could downregulate Tregs and the expression of PD-L1 in TME; hormone therapy could modulate ECM by reducing MMP9 and collagen; and all three therapies could increase immunostimulatory cytokines in the TME. Bottom: TME remodeling-induced treatment resistance: chemo/radiotherapy could upregulate WNT and Notch signaling in tumor cells by increasing WNT16B secretion from CAF, or Jagged1 expression in MSC and osteoblasts; chemo/radiotherapy could also disrupt vessels to induce hypoxia; all three therapies could recruit more TAM into TME; and hormone therapy could increase expression of resistant-promoting cytokines, such as IL-1b. MSC, mesenchymal stem cell.
Fig.3  Modulating TME to improve therapeutic responses. Immune-related strategies, such as immune checkpoint blockade, oncolytic virus, and oncolytic virus or vaccine based TAA delivery, could remodel TME by enhancing the activity of effector T cells, such as CTL, decreasing the activity of Tregs, and increasing tumor killing cytokines, such as INF-γ and TNF-α. Nanoparticles could modulate TME by disrupting or remodeling vessel growth to inhibit tumor growth or enhance drug delivery respectively. Nanoparticles could also target CAFs to decrease Wnt16 secretion. Moreover, nanoparticles conjugated with recombinant human hyaluronidase PH20 could digest ECM to improve drug delivery and reduce hypoxia. Other strategies such as nanoparticles loaded with laminin-mimic peptide could also mimic and reinforce ECM to prevent dissemination of tumor cells. TAA, tumor-associated antigen; NPs, nanoparticles.
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