The peritumor microenvironment: physics and immunity

Abstract

Cancer initiation and progression drastically alter the microenvironment at the interface between healthy and malignant tissue. This site, termed the peritumor, bears unique physical and immune attributes that together further promote tumor progression through interconnected mechanical signaling and immune activity. In this review, we describe the distinct physical features of the peritumoral microenvironment and link their relationship to immune responses. The peritumor is a region rich in biomarkers and therapeutic targets and thus is a key focus for future cancer research as well as clinical outlooks, particularly to understand and overcome novel mechanisms of immunotherapy resistance.

Keywords: immunotherapy; peritumor; physical immunity; physical oncology; tumor microenvironment.

Figure 1.. The highly interconnected physical landscape of the peritumor.

The four physical hallmarks of cancer – solid stress, fluid flow, stiffness, and microarchitecture – present as region-specific alterations in the peritumor. As changes occur within one hallmark, their downstream effects may create a positive feedback loop, potentially activating or exacerbating activity within other hallmarks. For example, increased solid stress (red arrows) from tumor growth results in radial and circumferential stress accumulating in the tissue. These stresses are capable of deforming cells and vasculature, while also contributing to the evolution of other physical hallmarks. A combination of leaky vasculature and faulty drainage contributes to a flow of fluid from the tumor through the peritumor. This flow (brown arrows) alters distributions of various molecular gradients (e.g., chemokines) and distributes them throughout the peritumor. Intriguingly, fluid flow and associated shear stresses activate cells (i.e., fibroblasts) as well as latent stores of growth factors, which have downstream implications in altering tissue stiffness and microarchitecture. Growth factors such as TGF-β activated by alterations in native stiffness (blue arrows) can exacerbate elevated matrix stiffness through such means as inducing fibroblast contraction, collagen realignment, or increases in matrix cross-linking. The latter two contribute to further increasing matrix stiffness. Finally, alterations in matrix and cellular microarchitecture (green arrows) arising from solid stress, fluid flow, matrix stiffness, and downstream activity of these pathways (i.e., fibroblast contraction, collagen realignment) contribute to the elevation of matrix stiffness. As shown by the mapping of physical interactions, these physical attributes are highly interconnected and foster the growth and development of each other.

Figure 2.. Profiling key physical hallmarks of the peritumor.

The peritumor exhibits alterations to four physical hallmarks: solid stress, fluid flow, stiffness, and microarchitecture. In regards to the tumor core, peritumor, and normal tissue, sample profiles of each hallmark demonstrate the distinct, region-specific characteristics of the peritumor. Solid stress arising from the growth of the tumor and resistance of the surrounding ECM acts in the circumferential (σ_θθ) and radial (σ_rr) directions. Consequently, single nuclei undergo varying degrees of nuclear compaction before reaching normal, spherical shapes within normal tissue. Fluid flow caused by leaky vasculature and faulty drainage mechanisms increase interstitial fluid pressure (IFP) at the tumor boundary, leading to positive fluid flow (V_f) from the tumor core that is capable of disseminating tumor components (e.g. cancer cells). Stiffness alterations within the peritumor may be detected using various elastography methods. Shown here are dramatically higher stiffnesses within the peritumor region of breast cancer tumors, represented by the color bar shown: highly stiff regions (red) are found in the peritumoral region compared to relatively less stiff (blue) regions towards healthy tissue. Finally, alterations in microarchitecture occur not only at the tumor surface but through the peritumoral stroma. Collagen images acquired using multiphoton microscopy and second harmonic generation show an alignment of collagen (green) at the boundary of a breast cancer tumor metastasized in the lung (pink). This gradient of alignment can be found near tumors undergoing growth and invasion as the peritumor region is modified to facilitate further cell movement.

Figure 3.. The physical landscape of the peritumor directly and indirectly affects the activity of immune cells to activate or suppress immunity.

Alterations to the four physical hallmarks of cancer – solid stress, fluid flow, stiffness, and microarchitecture – can have direct effects on immune cell activity (color-coded lines from attribute to specific cell type). These effects can be activating (sharp arrow) or inhibitory (blunt arrow) and are highly interconnected. Attributes may indirectly modulate immune cell behavior through intermediate signaling pathways. Prominent among these immunomodulatory molecules are: immune-inhibitory programmed death-ligand 1 (PD-L1), anti-inflammatory cytokine transforming growth factor β (TGF-β), matrix crosslinking enzyme lysyl oxidase (LOX), matrix remodeling matrix metalloproteinase-9 (MMP-9), and macrophage-specific transcription factors STAT3/6. The highly interrelated nature of the peritumor environment means that immune cells can be indirectly impacted by pathways which are up- or down-regulated by the physical microenvironment, which may then further activate (black sharp arrow) or inhibit (black blunt arrow) immune cells or immunomodulatory pathways. We illustrate the connections between the abundant elements that interact with mechano-immunity in the peritumor, and list the major components in Table 1 in the main text.