Fig. 2
From: Targeting purinergic pathway to enhance radiotherapy-induced immunogenic cancer cell death
The role of purinergic pathway in RT-induced ICD. A ATP in RT-induced T-cell-mediated ICD. Tumor cells release ATP (via cell lysis, channels such as PANX-1, and P2X7R), chemokines, and tumor antigens following RT to recruit immature DCs to TIME. ATP then binds to its receptors (P2XR/P2YR) on immature DCs leading to their activation. These DCs can take up and process tumor antigens released from dying tumor cells to transform into mature DCs. Mature DCs can then migrate to tumor-draining lymph nodes (TDLN), where DCs secret IL-1β, IL-6, TNF-α, and IFN-γ and cross-present tumor antigen peptides by MHC I to stimulate T-cell differentiation to CD8+ CTLs. CTLs can then migrate to the tumor site and maybe remote sites to recognize and kill residue tumor cells by releasing perforin, granzyme B, and/or through the interaction of the Fas/FasL signaling. B Production of ADO leads to a post-RT immunosuppressive TIME. Hypoxia induced by RT upregulates the expression of HIF1-α, leading to the overexpression of CD39 and CD73 of cancer cells to hydrolyze large amounts of ATP to ADO in TIME. ADO is contributed to an immunosuppressive TIME to enable tumor cells to escape immune-surveillance by suppressing the effector immune components including Teff, DCs, NK cells, and neutrophils, while enhancing the activity of immunosuppressive cell subsets including Treg, M2-macrophage, and MDSC, in which pharmacological antagonists against A2AR and/or A2BR as well as blockades inhibiting CD39 and CD73 can reverse ADO-induced immunosuppressive TIME to favor antitumor immunity. A2AR, A2A adenosine receptor; A2BR, A2B adenosine receptor; ADO, adenosine; AMP, adenosine monophosphate; ATP, adenosine triphosphate; CTL, cytotoxic T lymphocyte; CTLA4, cytotoxic T-lymphocyte associated protein 4; DC, dendritic cell; Fas, factor-related apoptosis; FasL, factor-related apoptosis ligand; ICD, immunogenic cell death; IFN-γ, interferon gamma; IL-1β, interleukin-1 beta; IL-2, interleukin-2; IL-6, interleukin-6; IL-10, interleukin-10; IL-12, interleukin-12; MHC I, major histocompatibility complex class I; P2X7R, P2X7 purinergic receptor; PANX-1, pannexin 1; PD1, programmed cell death protein 1; PGE2, prostaglandin E2; RT, radiotherapy; TCR, T-cell receptor; TDLN, tumor-draining lymph node; TGF-β, transforming growth factor beta; TNF-a, tumor necrosis factor alpha; VEGF, vascular endothelial growth factor. Partly created by Figdraw (www.figdraw.com)