Targeting the CD47/thrombospondin-1 signaling axis regulates immune cell bioenergetics in the tumor microenvironment to potentiate antitumor immune response

Abstract

BackgroundCD47 is an integral membrane protein that alters adaptive immunosurveillance when bound to the matricellular glycoprotein thrombospondin-1 (TSP1). We examined the impact of the CD47/TSP1 signaling axis on melanoma patient response to anti-PD-1 therapy due to alterations in T cell activation, proliferation, effector function, and bioenergetics.MethodsA syngeneic B16 mouse melanoma model was performed to determine if targeting CD47 as monotherapy or in combination with anti-PD-1 impacted tumor burden. Cytotoxic (CD8+) T cells from Pmel-1 transgenic mice were used for T cell activation, cytotoxic T lymphocyte, and cellular bioenergetic assays. Single-cell RNA-sequencing, ELISA, and flow cytometry was performed on peripheral blood mononuclear cells and plasma of melanoma patients receiving anti-PD-1 therapy to examine CD47/TSP1 expression.ResultsHuman malignant melanoma tissue had increased CD47 and TSP1 expression within the tumor microenvironment compared with benign tissue. Due to the negative implications CD47/TSP1 can have on antitumor immune responses, we targeted CD47 in a melanoma model and observed a decrease in tumor burden due to increased tumor oxygen saturation and granzyme B secreting CD8+ T cells compared with wild-type tumors. Additionally, Pmel-1 CD8+ T cells exposed to TSP1 had reduced activation, proliferation, and effector function against B16 melanoma cells. Targeting CD47 allowed CD8+ T cells to overcome this TSP1 interaction to sustain these functions. TSP1 exposed CD8+ T cells have a decreased rate of glycolysis; however, targeting CD47 restored glycolysis when CD8+ T cells were exposed to TSP1, suggesting CD47 mediated metabolic reprogramming of T cells. Additionally, non-responding patients to anti-PD-1 therapy had increased T cells expressing CD47 and circulating levels of TSP1 compared with responding patients. Since CD47/TSP1 signaling axis negatively impacts CD8+ T cells and non-responding patients to anti-PD-1 therapy have increased CD47/TSP1 expression, we targeted CD47 in combination with anti-PD-1 in a melanoma model. Targeting CD47 in combination with anti-PD-1 treatment further decreased tumor burden compared with monotherapy and control.ConclusionCD47/TSP1 expression could serve as a marker to predict patient response to immune checkpoint blockade treatment, and targeting this pathway may preserve T cell activation, proliferation, effector function, and bioenergetics to reduce tumor burden as a monotherapy or in combination with anti-PD-1.

HX009, a novel BsAb dual targeting PD1 x CD47, demonstrates potent anti-lymphoma activity in preclinical models

“…However, recent observations increasingly pointed to the role of CD47 targeting on TME, e.g. T eff cells 37,[53][54][55][56] . With regard to the potential CD47 targeting MOAs of HX009, the anti-lymphoma effect could be attributed to targeting to CD47 either on tumor cells or on T eff CD47 (or even other immune cells in TME), or on both.…”

Unlocking the potential of T‐cell metabolism reprogramming: Advancing single‐cell approaches for precision immunotherapy in tumour immunity

“…Similarly, CD47 overexpression in the TME allows tumour cells to avoid immune surveillance. Blocking T‐cell CD47 expression stimulates a sustained increase in Teff glycolytic efficiency and reestablishes the classical cytotoxic phenotype 180 . Moreover, clinical trials have demonstrated that a combination of CD47 mAbs and ICIs results in a reduced tumour burden and prolonged survival 181 .…”

Opportunities and challenges of CD47-targeted therapy in cancer immunotherapy

“…Furthermore, CD47 interacts with TSP-1, an extracellular matrix protein expressed in the TME [44]. TSP 1 exerts inhibitory effects on angiogenesis through multiple mechanisms, including the stimulation of endothelial cell apoptosis, inhibition of endothelial cell migration and proliferation, and regulation of vascular endothelial growth factor (VEGF) bioavailability and activity [45].…”

“…CD47-mediated signaling between cancer and stromal cells CD47-mediated signaling plays a critical role in regulating tumor growth and progression by facilitating communication between cancer cells and stromal cells in the TME. It interacts with TSP-1, which is expressed on stromal cells such as endothelial cells and fibroblasts in the TME [44]. This interaction can potentially influence downstream signaling events that involve Akt/mTOR and NF-κB pathways, which promote tumor cell survival, invasion, and angiogenesis while inhibiting immune cell function.…”