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Review
. 2018 Jul 3;6(1):65.
doi: 10.1186/s40425-018-0376-0.

Tumor matrix remodeling and novel immunotherapies: the promise of matrix-derived immune biomarkers

Muhammad Umair Mushtaq  1   2 , Athanasios Papadas  1   2 , Adam Pagenkopf  1   2 , Evan Flietner  1   2 , Zachary Morrow  1   2 , Sibgha Gull Chaudhary  1   2 , Fotis Asimakopoulos  3   4
Affiliations
Review

Tumor matrix remodeling and novel immunotherapies: the promise of matrix-derived immune biomarkers

Muhammad Umair Mushtaq et al. J Immunother Cancer. .

Abstract

Recent advances in our understanding of the dynamics of cellular cross-talk have highlighted the significance of host-versus-tumor effect that can be harnessed with immune therapies. Tumors exploit immune checkpoints to evade adaptive immune responses. Cancer immunotherapy has witnessed a revolution in the past decade with the development of immune checkpoint inhibitors (ICIs), monoclonal antibodies against cytotoxic T lymphocyte antigen 4 (CTLA-4) and programmed cell death protein 1 (PD-1) or their ligands, such as PD1 ligand 1 (PD-L1). ICIs have been reported to have activity against a broad range of tumor types, in both solid organ and hematologic malignancy contexts. However, less than one-third of the patients achieve a durable and meaningful treatment response. Expression of immune checkpoint ligands (e.g., PD-L1), mutational burden and tumor-infiltrating lymphocytes are currently used as biomarkers for predicting response to ICIs. However, they do not reliably predict which patients will benefit from these therapies. There is dire need to discover novel biomarkers to predict treatment efficacy and to identify areas for development of combination strategies to improve response rates. Emerging evidence suggests key roles of tumor extracellular matrix (ECM) components and their proteolytic remodeling products in regulating each step of the cancer-immunity cycle. Here we review tumor matrix dynamics and matrix remodeling in context of anti-tumor immune responses and immunotherapy and propose the exploration of matrix-based biomarkers to identify candidates for immune therapy.

Keywords: Adaptive immune response; Immune biomarkers; Immune checkpoint inhibitors; Immunotherapy; Matrix remodeling; Tumor microenvironment.

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Figures

Fig. 1
Fig. 1
Extracellular matrix (ECM) and the inflamed tumor microenvironment. The TME is an intricate milieu of cells hosting the tumor, including infiltrating myeloid and lymphoid cells, stromal and mesenchymal cells, and ECM components. Matrix remodeling shapes the inflamed immune microenvironment. Tumor-infiltrating Tregs and regulatory myeloid cells, including MDSCs, TAMs and TANs, promote a tolerogenic TME. Tumor-infiltrating CTLs, dendritic cells, matrix components (like CAFs, HA, HSPGs, SLRPs, and VCAN), matrikines (e.g., versikine) and matrix-remodeling enzymes (MMPs and ADAMTSs) play a vital role in the generation and amplification of the host immune response. Abbreviations: TME; tumor microenvironment, ECM; extracellular matrix, CTL; cytotoxic lymphocytes, Treg; regulatory T cells, TAM 1 and 2; tumor-associated macrophages types 1 and 2, TAN 1 and 2; tumor-associated neutrophils types 1 and 2, MDSC; myeloid-derived-suppressor cells, PDL1; programmed cell death protein ligand 1, CAFs; cancer-associated fibroblasts, SLRPs; small leucine-rich proteoglycans, HA; hyaluronan, HSPGs; heparin sulfate proteoglycans, VCAN; versican, MMPs; matrix metalloproteinases, ADAMTSs, A disintegrin and metalloproteinase with thrombospondin motifs
Fig. 2
Fig. 2
Multiple roles of the extracellular matrix (ECM) in modulating the cancer-immunity cycle. The cancer-immunity cycle progresses through tumor cell death and release of tumor antigens, tumor antigen presentation, priming and activation of T cells, trafficking of T cells, T-cell infiltration of tumor and recognition of tumor cells by effectors. Matrix remodeling shapes the inflamed immune microenvironment and plays a vital role at each step of the cancer-immunity cycle. Tumor antigen presentation and generation of the adaptive immune response depends on tumor-infiltrating Batf3-cDCs, matrikines, cytokines and chemokines of CCL and CXCL family. Versikine promotes differentiation of the potent immune-stimulator Batf3-cDCs. STING pathway activation, elicited by tumor cell-derived DNA, results in type I interferon (IFN) production and DC maturation. Endothelial cells, adhesion molecules and chemokines modulate trafficking of leukocytes. Stromal cells, including endothelial cells, pericytes and CAFs, and extracellular matrix components including collagens, GPs, GAGs and PGs, regulate infiltration and polarization of immune cells. Matrikines, cytokines and laminins regulate priming and activation of T cells. Matrix proteases and matrikines, including versikine, exert direct effects on immune cell polarization and activation. ICIs block immune checkpoints to induce anti-tumor immunity; however, the tumor matrix regulates generation and proliferation of the sustained host immune response. Matrix-derived immune biomarkers promise an innovative approach to predict response to novel immunotherapies. Abbreviations: Batf3-cDCs; Batf3-dependent classical dendritic cells, IRF8; interferon regulatory factor 8, IFN; interferon, STING; stimulator of interferon genes, CAFs; cancer-associated fibroblasts, GPs; glycoproteins, GAGs; glycosaminoglycans, PGs; proteoglycans, VCAN; versican, DCs; dendritic cells, APCs; antigen presenting cells
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