LRG1 destabilizes tumor vessels and restricts immunotherapeutic potency

Abstract

Vascular dysfunction contributes to the pro-oncogenic tumor microenvironment and impedes the delivery of therapeutics. Normalizing of the tumor vasculature has therefore become a potential therapeutic objective. We previously reported that the secreted glycoprotein, leucine-rich α-2-glycoprotein 1 (LRG1), contributes to the formation of pathogenic neovascularization. Here we show that in mouse models of cancer, Lrg1 is induced in tumor endothelial cells. We demonstrate that the expression of LRG1 impacts on tumor progression as Lrg1 deletion or treatment with a LRG1 function-blocking antibody inhibited tumor growth and improved survival. Inhibition of LRG1 increased endothelial cell pericyte coverage and improved vascular function resulting in significantly enhanced efficacy of cisplatin chemotherapy, adoptive T-cell therapy and immune checkpoint inhibition (anti-PD1) therapy. With immunotherapy, LRG1 inhibition led to a significant shift in the tumor microenvironment from being predominantly immune silent (cold) to immune active (hot). LRG1 therefore drives vascular abnormalization and its inhibition represents a novel and effective means of improving the efficacy of cancer therapeutics.

Leucine-rich alpha-2-glycoprotein 1 (LRG1) as a novel ADC target

“…The lack of effectiveness contrasts with a previous report showing significant tumour inhibition following LRG1 blockade with the parent antibody 15C4. 21 This is most likely due to the sub-optimal dose of 20 mg kg À1 of Magacizumab used in this study and the less frequent administration. However, ADC 5 administered on its own and in combination with cisplatin gave a pronounced tumour growth delay which was evident even after receiving just a single treatment dose, and extended overall survival from 24 days as seen for untreated mice to 30 and 34 days respectively (Fig.…”

“…Hence, a study was conducted where the novel ADC 5 was compared against a number of treatments including a suboptimal dosing regimen of the native parent antibody Magacizumab and a maximum tolerated dose, as determined by O'Connor et al 21 of the chemotherapeutic agent cisplatin. In order to obtain more insights into the susceptibility of ADC products to proteolytic cleavage, ADC 5 was also investigated in combination with the chemotherapeutic agent cisplatin, where the ADC and cisplatin were administered as a single injection at the same time.…”

“…38,59 Such a high injected dose of ADC would also ensure that the injected dose is sufficient to exceed what may be adsorbed by the circulating LRG1 pool. This dose of cisplatin was selected as it has been demonstrated as the maximum tolerated dose by O'Connor et al 21 in the B16F0 subcutaneous model. Tumours were measured and mice were weighed regularly throughout the duration of the study.…”

“…[28][29][30] As LRG1 is dispensable for developmental angiogenesis, 20 attempts to neutralise the pro-angiogenic and vasculopathic activity of LRG1 have been investigated and have led to the development of a function-blocking fully humanised IgG4 antibody against LRG1. 31 The Moss and Greenwood groups have shown that inhibiting LRG1 reverses its detrimental effects on the vasculature and leads to partial restoration of normal vascular function 21,31 and consequently improvement in the delivery of cytotoxic and immune co-therapies. 21 These observations suggest that LRG1 is a promising therapeutic target in pathological angiogenesis, particularly as blockade of this protein targets an orthogonal pathway to VEGF and, in the context of TGFb, inhibits the activator of the pathogenic signalling arm without interfering with homeostatic activities.…”

“…31 The Moss and Greenwood groups have shown that inhibiting LRG1 reverses its detrimental effects on the vasculature and leads to partial restoration of normal vascular function 21,31 and consequently improvement in the delivery of cytotoxic and immune co-therapies. 21 These observations suggest that LRG1 is a promising therapeutic target in pathological angiogenesis, particularly as blockade of this protein targets an orthogonal pathway to VEGF and, in the context of TGFb, inhibits the activator of the pathogenic signalling arm without interfering with homeostatic activities. The expression of LRG1 in many cancers and the presence of LRG1 at high concentrations in the tumour microenvironment makes it a promising target.…”