Abstract
Collagens in the extracellular matrix (ECM) provide a physical barrier to tumor immune infiltration, while also acting as a ligand for immune inhibitory receptors. Transforming growth factor-β (TGF-β) is a key contributor to shaping the ECM by stimulating the production and remodeling of collagens. TGF-β activation signatures and collagen-rich environments have both been associated with T cell exclusion and lack of responses to immunotherapy. Here, we describe the effect of targeting collagens that signal through the inhibitory leukocyte-associated immunoglobulin-like receptor-1 (LAIR-1) in combination with blockade of TGF-β and programmed cell death ligand 1 (PD-L1). This approach remodeled the tumor collagenous matrix, enhanced tumor infiltration and activation of CD8+ T cells, and repolarized suppressive macrophage populations, resulting in high cure rates and long-term tumor-specific protection across murine models of colon and mammary carcinoma. The results highlight the advantage of direct targeting of ECM components in combination with immune checkpoint blockade therapy.
Highlights
Immune checkpoint blockade (ICB) therapies targeting the programmed cell death 1 receptor (PD-1) or its ligand programmed cell death ligand 1 (PD-L1) have shown unprecedented clinical benefit across various cancer types, yet durable responses have been achieved only in a limited subset of patients [1]
polymorphonuclear cells (PMNs) in the NC410 plus bintrafusp alfa group had significantly lower expression of Cxcl2 (Figure 6, F and G), which encodes a chemokine known to attract PMNs and myeloidderived suppressor cells and to modulate tumor cell plasticity [25, 26], compared with all other groups. These results suggested that while NC410 plus Transforming growth factor-β (TGF-β) sequestration mediated by the TGF-β trap control agent can promote increased frequencies of natural killer (NK) and CD8+ T cells, blockade of LAIR-1, PD-1/PD-L1, and TGF-β pathways synergizes for optimal immune cell activation and repolarization of macrophages in the tumor microenvironment (TME)
This work describes a combinatorial immunotherapy approach consisting of neutralization of PD-L1 and TGF-β with blockade of collagen/LAIR-1 signaling
Summary
Immune checkpoint blockade (ICB) therapies targeting the programmed cell death 1 receptor (PD-1) or its ligand PD-L1 have shown unprecedented clinical benefit across various cancer types, yet durable responses have been achieved only in a limited subset of patients [1]. Analyses of tumor biomarkers in clinical studies across various tumor types have identified factors that associate with response to ICB, including expression of PD-L1 on both tumor cells and tumor-infiltrating lymphocytes (TILs), tumor mutational burden, and TIL density, location, and activation [2]. Beyond these factors, the presence of a collagen-dense extracellular matrix (ECM) and high numbers of immunosuppressive myeloid cell populations are increasingly being recognized as critical determinants of tumor responses to ICB therapy [3]. Functioning as a physical barrier to immune cell infiltration into the tumor [7], a collagen-dense ECM has been
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