Tumors vs. Chronic Wounds: An Immune Cell's Perspective

Abstract

The wound repair program is tightly regulated and coordinated among different cell constituents including epithelial cells, fibroblasts, immune cells and endothelial cells following consecutive steps to ensure timely, and proper wound closure. Specifically, innate and adaptive immune cells are pivotal participants that also closely interact with the vasculature. Tumors are portrayed as wounds that do not heal because they undergo continuous stromal remodeling and vascular growth with immunosuppressive features to ensure tumor propagation; a stage that is reminiscent of the proliferative resolution phase in wound repair. There is increasing evidence from mouse model systems and clinical trials that targeting both the immune and vascular compartments is an attractive therapeutic approach to reawaken the inflammatory status in the "tumor wound" with the final goal to abrogate tumor cells and invigorate tissue homeostasis. In this review, we compare the implication of immune cells and the vasculature in chronic wounds and tumor wounds to underscore the conceptual idea of transitioning tumors into an inflammatory wound-like state with antiangiogenic immunotherapies to improve beneficial effects in cancer patients.

Keywords: antiangiogenic immunotherapy; endothelial cells; macrophages; myeloid cells; neutrophils; tumor vessels; wound repair.

Figure 1

Tumors hijack the wound repair program: Chronic wound vs. tumor wound. Usually wound healing is manifested in several sequential steps after injury referred to as inflammation, proliferation-resolution, and remodeling phase. Immune cells are key regulators in the wound repair program. In the inflammation phase, neutrophils kill microbes and macrophages phagocytose apoptosing neutrophils, while skin-resident or infiltrating T cells produce IL-17, IL-22, and TNF α to amplify the host defense response. During the proliferation phase, macrophages switch to an anti-inflammatory phenotype (M_supp). M_supp macrophages, N_supp neutrophils (or tumor-associated neutrophil, TANs), Tregs and other immunosuppressive cells may help to attenuate the inflammation response and facilitate resolution and tissue remodeling. Chronic wounds get trapped in the inflammation phase, exacerbate inflammation and thus, hinder tissue repair. Tumors, on the other hand, hijack the proliferative/remodeling program and provide signals that create a continuous angiogenic and immunosuppressive environment enabling tumors to grow and escape immune surveillance. Therefore, tumors remain in the proliferative phase upon the onset of angiogenesis. Antiangiogenic immunotherapies induce an inflammation program in tumors that reawakens and boosts an anti-tumor response. The ultimate goal is to create a homeostatic situation in which tumor cells are eliminated and a normal tissue architecture is achieved. CAF, Cancer-associated fibroblast; CTL, cytotoxic T lymphocyte; DC, dendritic cell; DCreg, regulatory DC; ECM, extracellular matrix; MDSC, myeloid-derived suppressor cells; Mono, monocyte; M_stim, immunostimulatory macrophage (M1-like); M_supp, immunosuppressive macrophage (M2-like); N_stim, immunostimulatory neutrophil (N1-like); N_supp, immunosuppressive neutrophil (TAN); pDC, plasmacytoid DC; Th, T helper cell; Treg, regulatory T cell.

Figure 2

Regulatory network of the tumor immune microenvironment. The tumor microenvironment facilitates cross-talks between immunosuppressive macrophages, MDSCs, N_supp, Tregs and CD4⁺ Th2 cells that promotes angiogenesis, immunosuppression, and tumor progression. During the course of antiangiogenic and/or immunotherapy, myeloid cells including macrophages can switch to an inflammatory phenotype, and cooperate with CD8⁺ CTLs and CD4⁺ Th1 cells to generate an anti-tumor response and promote vessel pruning and normalization. Ang2, angiopoietin 2; CAF, Cancer-associated fibroblast; CTL, cytotoxic T lymphocyte; DC, dendritic cell; DCreg, regulatory DC; FGF, Fibroblast growth factor; IFN, interferon; IL, interleukin; M-CSF, Macrophage colony-stimulating factor; MDSC, myeloid-derived suppressor cells; MMP, Matrix metalloproteinases; M_stim, immunostimulatory macrophage (M1-like); M_supp, immunosuppressive macrophage (M2-like); N_stim, immunostimulatory neutrophil (N1-like); N_supp, immunosuppressive neutrophil (TAN); PDGF, Platelet-derived growth factor; PlGF, Placental growth factor; TAN, Tumor-associated neutrophil; TGF-β, Transforming growth factor beta; Th, T helper cell; Treg, regulatory T cell; VEGFA, Vascular endothelial growth factor A. Cells in orange or red color represent immunostimulation/type 1 immunity/anti-angiogenic status, while cells in green/blue represent immunosuppression/type 2 immunity/pro-angiogenic status.