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.
Highlights
The adaptive immune response protects against foreign threats, including infections and tumors
Initial antigen-mediated activation of T cells is modulated by several regulatory mechanisms, including engagement co-stimulatory signals like the binding of CD28 on T cells to CD80/B7-1 and/or CD86/B7-2 on antigen-presenting cells
Immune-cell trafficking in the tumor microenvironment (TME): mechanisms and impact on immunotherapy responses The trafficking of cytotoxic lymphocytes (CTL), Regulatory T cells (Tregs) and immune-suppressive myeloid cells is dependent on several factors encountered in the extracellular matrix (ECM), including matrix components, vascular endothelial cells and cell surface glycoproteins [105, 109]
Summary
The adaptive immune response protects against foreign threats, including infections and tumors. Brisk CTL infiltrates at time of progression in patients on immune checkpoint blockade has been noted, suggesting that effector immune cells are impaired by the TME leading to therapeutic resistance [54]. Type 1 TAMs (M1) produce immune-stimulatory cytokines, like IL6, IL12 and CXCL9, that promote infiltration of CTLs whereas type 2 TAMs (M2) support tumor growth by diverse pathways, including production of angiogenic factors like IL-10 and CCL22, matrix remodeling by proteases, and inhibition of CTLs and DCs [79].
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