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Review
. 2016 Apr;4(4):269-78.
doi: 10.1158/2326-6066.CIR-16-0011.

Can Targeting Stroma Pave the Way to Enhanced Antitumor Immunity and Immunotherapy of Solid Tumors?

Ellen Puré  1 , Albert Lo  2
Affiliations
Review

Can Targeting Stroma Pave the Way to Enhanced Antitumor Immunity and Immunotherapy of Solid Tumors?

Ellen Puré et al. Cancer Immunol Res. 2016 Apr.

Abstract

Solid tumors are complex organ-like structures. The potential of normal neighboring cells to contribute to the initiation, progression, and metastasis of epithelial-derived carcinomas has long been appreciated. However, the role of host cells has proven complex. Through multiple local and systemic mechanisms, nontransformed host cells can promote transition from a tumor-resistant to tumor-permissive environment, drive neoplastic transformation of epithelial cells, promote tumor growth, progression, and metastasis, but also constrain tumorigenesis. This complexity reflects the spatially and temporally dynamic involvement of multiple cell types and processes, including the development and recruitment of inflammatory, immune, endothelial, and mesenchymal stromal cells, and the remodeling of extracellular matrix. Our mechanistic understanding, as well as our ability to translate advances in our understanding of these mechanisms for therapeutic benefit, is rapidly advancing. Further insights will depend on delineating pathways that mediate the communication networks between inflammatory and immune cells with tumor and mesenchymal stromal cells and extracellular matrix. Here, we discuss the diversity of mesenchymal stromal cell populations and how context can dictate either their promotion or constraint of tumorigenesis. We review evidence for plasticity that allows for reprogramming of stromal cells and how tumor immunogenicity and desmoplasia influence the balance of immune-independent and immune-dependent regulation of tumor growth. The pivotal roles of matrix and mesenchymal stromal cells in modulating inflammation, antitumor immunity, and the efficacy of immune-based therapies are discussed. These concepts have emerged from data obtained from tumors of multiple organs, but we focus mostly on studies of pancreatic ductal adenocarcinomas.

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Conflict of interest statement

Disclosures of Potential Conflicts of Interest

The laboratory of E. Puré received research support from Novartis and shares inventor status on a pending patent.

Figures

FIGURE 1
FIGURE 1. Evolution of tumor stroma and its immune-dependent and immune-independent control of tumor growth
(A) Overview. (B) Multiple stromal cell types found in normal tissues, including fibroblasts, mesenchymal stem cells, adipocytes, endothelial cells, and epithelial cells can (trans)differentiate into cancer-associated fibroblasts (CAFs)/stromal cells. This stromagenic switch that transitions a tumor suppressive environment to a tumor promoting environment is driven by multiple factors, including those indicated, and may be reversible based on recent evidence of reprogramming following treatment with the vitamin D receptor agonist calcitriol. Two prominent subclasses are myofibroblasts, characterized by the expression of proteins of the contractile apparatus such as α-SMA, and FAP+ reactive fibroblasts. These two subpopulations are distinct but overlap to varying degrees in different tumor types and can have opposing effects on tumorigenesis, at least in pancreatic cancer. (C) The products regulated in CAFs relative to normal fibroblasts that promote cell proliferation: a shift from oxidative phosphorylation to glycolysis, matrix remodeling, angiogenesis, inflammation, and immune suppression in the tumor microenvironment are shown. The indicated pathways regulate tumor growth through immune-independent (D) and immune-dependent (E) mechanisms.
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