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

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. Herein 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 reprograming 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, anti-tumor 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 most on studies of pancreatic ductal adenocarcinomas (PDA).

Honokiol suppresses pancreatic tumor growth, metastasis and desmoplasia by interfering with tumor–stromal cross-talk

“…Another unique characteristic of PC is existence of high desmoplasia, which is suggested to promote lymphangiogenesis, metastasis and chemoresistance (22,24). It is also being explored as a factor that influences the balance between immune-dependent and immune-independent regulation of tumor growth (23). In our study, we observed an inhibitory effect of HNK on desmoplasia, as characterized by reduced secretion of extracellular matrix protein (collagen I) and diminished staining for myofibroblast marker (a-SMA).…”

“…Extensive desmoplasia is a fundamental characteristic of pancreatic tumors, which has been suggested to be of significance from the pathobiological and clinical standpoints (22)(23)(24). Therefore, we next examined the effect of HNK on the desmoplastic reaction in orthotopic pancreatic tumors.…”

In Silico Modeling of Immunotherapy and Stroma-Targeting Therapies in Human Colorectal Cancer

“…Currently, several experimental therapies in the clinic aim to target the stroma. Indeed, most prominent are approaches with enzymes that aim to enhance the permeability of stroma (4,5,48). Our data show that these approaches can be very effective but can also have adverse effects that need to be considered before clinical development of new substances.…”

“…Additionally, many more drugs are currently investigated in clinical trials, especially combination therapies aiming at the stromal compartment (4,5). These approaches act on the complex interactions in the tumor microenvironment, as we could show recently in macrophage-targeted immunotherapies (6).…”

Targeting tumor tolerance: A new hope for pancreatic cancer therapy?

“…However, in order to appropriately describe mechanisms of stromal immune regulation, it is also relevant to discuss the degree to which the "stromal compartment" actually represents a heterogeneous cellular population. Indeed, the work of Dr. Puré and colleagues reinforce the concept of stromal cell plasticity, suggesting stromal cells expressing fibroblast activation protein (FAP) represent a mesenchymal stem cell niche responsible for much of the local immunoregulatory signals compared to the terminally differentiated αSMA + myofibroblast (Lo, et al, 2015;Pure, et al, 2016). Multiple animal models have demonstrated enhanced antitumor immunity when FAP-expressing cells are conditionally depleted (Feig, et al, 2013) or therapeutically targeted (Lo, et al, 2015;L.…”