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

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.

Extracellular Matrix in the Tumor Microenvironment and Its Impact on Cancer Therapy

“…VEGF-A also is able to recruit T regs that express NRP1, a VEGF coreceptor, and can directly suppresses activation of T cells (Gavalas et al, 2012;Powell et al, 2018). Consequently, tumor ECM remodeling, stabilization, and accumulation are increasingly recognized as crucial factors controlling infiltration and also differentiation, activation, and polarization of immune cells in the TME (Mushtaq et al, 2018). For the distribution of immunomodulatory drugs, the same consideration apply as for other antineoplastic drugs.…”

Extracellular Protease ADAMTS1 Is Required at Early Stages of Human Uveal Melanoma Development by Inducing Stemness and Endothelial-Like Features on Tumor Cells

“…The tumor microenvironment (TME) has been highlighted as a key player during tumor development, providing specific signals that support cell invasion, proliferation and phenotypic plasticity [1]. TME is extremely dynamic, involving all its cellular and extracellular constituents, and its full understanding still requires a multilayered research to identify new targets and biomarkers [2]. On the extracellular side, the actions of a variety of proteases contributed to such dynamism by the alteration of multiple pathways with impact during all stages of neoplasias.…”

Tumors attenuating the mitochondrial activity in T cells escape from PD-1 blockade therapy

“…For successful PD-1 blockade therapy, the “tumor-immunity cycle” needs to operate smoothly (Chen & Mellman, 2013; Pio, Ajona, Ortiz-Espinosa, Mantovani, & Lambris, 2019). Hindrance in the pathway at any steps of antigen recognition, activation, recruitment and killing at the tumor site, DLN or blood stream would lead to the unresponsive state (Mushtaq et al, 2018). DLN is generally considered as a place where naïve T cells are primed to effector T cells.…”