Combined Blockade of GARP:TGF-β1 and PD-1 Increases Infiltration of T Cells and Density of Pericyte-Covered GARP+ Blood Vessels in Mouse MC38 Tumors

Abstract

When combined with anti-PD-1, monoclonal antibodies (mAbs) against GARP:TGF-β1 complexes induced more frequent immune-mediated rejections of CT26 and MC38 murine tumors than anti-PD-1 alone. In both types of tumors, the activity of anti-GARP:TGF-β1 mAbs resulted from blocking active TGF-β1 production and immunosuppression by GARP-expressing regulatory T cells. In CT26 tumors, combined GARP:TGF-β1/PD-1 blockade did not augment the infiltration of T cells, but did increase the effector functions of already present anti-tumor T cells. Here we show that, in contrast, in MC38, combined GARP:TGF-β1/PD-1 blockade increased infiltration of T cells, as a result of increased extravasation of T cells from blood vessels. Unexpectedly, combined GARP:TGF-β1/PD-1 blockade also increased the density of GARP+ blood vessels covered by pericytes in MC38, but not in CT26 tumors. This appears to occur because anti-GARP:TGF-β1, by blocking TGF-β1 signals, favors the proliferation of and expression of adhesion molecules such as E-selectin by blood endothelial cells. The resulting densification of intratumoral blood vasculature probably contributes to increased T cell infiltration and to the therapeutic efficacy of GARP:TGF-β1/PD-1 blockade in MC38. We conclude from these distinct observations in MC38 and CT26, that the combined blockades of GARP:TGF-β1 and PD-1 can exert anti-tumor activity via multiple mechanisms, including the densification and normalization of intratumoral blood vasculature, the increase of T cell infiltration into the tumor and the increase of the effector functions of intratumoral tumor-specific T cells. This may prove important for the selection of cancer patients who could benefit from combined GARP:TGF-β1/PD-1 blockade in the clinics.

Limited impact of cancer-derived gangliosides on anti-tumor immunity in colorectal cancer

“…In our study, we also observed a reduction in the number of blood vessels in MC38-ST3Gal5 KO tumors, however it did not impact tumor growth. Prior research revealed that endothelial cells forming the blood vessels in MC38 tumors were distinct from endothelial cells found in the blood vasculature of CT26 tumors ( Bertrand et al. 2021 ), which might explain the differential effect of ST3Gal5 on blood vessel formation in our study.…”

Nuclear Glycoprotein A Repetitions Predominant (GARP) Is a Common Trait of Glioblastoma Stem-like Cells and Correlates with Poor Survival in Glioblastoma Patients

“…The principal binding partner of GARP, TGF-β, has been shown to induce the expression of PD-L1, but it remains unclear if GARP expression can as well [55,56]. It is worth noting that the simultaneous targeting of GARP, TGF-β1, and PD-1 has been shown to be an effective combination therapy, capable of restoring T effector cell function and overcoming resistance to PD-1/PD-L1 blockade [57,58]. Future studies are planned to clarify the relationship between GARP, PD-L1, and differentiation to determine if their contribution to immune suppression is responsible for the observed reduction in patient survival.…”

Targeting vascular normalization: a promising strategy to improve immune–vascular crosstalk in cancer immunotherapy

“…The blocking of TGF-β1 signaling favors the proliferation and expression of adhesion molecules, such as E-selectin in ECs, leading to the densification and normalization of the vasculature within the tumors. Moreover, the co-blockade of TGF-β1/PD-1 increased the density of blood vessels covered by pericytes ( 204 ). CD4 + and CD8 + T cells effectively mediate vascular normalization in breast cancer models ( 108 , 205 ).…”