PEGylated arginine deiminase can modulate tumor immune microenvironment by affecting immune checkpoint expression, decreasing regulatory T cell accumulation and inducing tumor T cell infiltration

Abstract

PEGylated arginine deiminase (ADI-PEG 20) is being investigated in clinical studies in arginine auxotrophic cancers and is well-tolerated. The anti-tumor properties of ADI-PEG 20 have been extensively investigated - ADI-PEG 20 inhibits the growth of auxotrophic cancers in vitro and in vivo - however, its impact on immune cells is largely unknown. Here we report the potential impact of ADI-PEG 20 on the tumor immune microenvironment. ADI-PEG 20 induced immunosuppressive programmed death-ligand 1 expression on some cancer cells in vitro, but the magnitude of the increase was cell line dependent and in most relatively small. Using healthy donor human peripheral blood mononuclear cells (PBMCs) we discovered that when present during initiation of T cell activation (but not later on) ADI-PEG 20 can inhibit their differentiation after early activation stage manifested by the expression of CD69 marker.In vivo, ADI-PEG 20 induced tumor T-cell infiltration in a poorly immunogenic syngeneic mouse melanoma B16-F10 model and reduced its growth as a single agent or when combined with anti-PD-1 mAb. It was also effective by itself or in combination with anti-PD-L1 mAb in CT26 colon carcinoma syngeneic model.

Arginine-Depleting Enzymes – An Increasingly Recognized Treatment Strategy for Therapy-Refractory Malignancies

“…Metabolic fitness and T-cell survival are particularly crucial in anti-tumor responses. Only recently, Brin et al described no adverse side effects on human peripheral blood mononuclear cells upon arginine starvation [90]. This study thus supports recent findings stating that ADI-PEG20 does not significantly impair the viability of normal cells -especially when high amounts of citrulline are present [89].…”

“…Though not clinically proven, ADI-PEG20 boosted tumor immunogenicity in a syngeneic B16-F10-melanoma mouse model and thus contradicts previous findings [90]. Effects were further enhanced when ADI-PEG20 was combined with immune-checkpoint inhibiting antibody PD-1 [90]. To the best of our knowledge, neither study examined the influence on antigen-presenting and antibody-producing B-cells in the context of arginine deprivation.…”

“…Since tumor patients often have high amounts of primed T cells infiltrating their tumors, interference of ADI-PEG20 with those cells is rather unlikely. Though not clinically proven, ADI-PEG20 boosted tumor immunogenicity in a syngeneic B16-F10-melanoma mouse model and thus contradicts previous findings [90]. Effects were further enhanced when ADI-PEG20 was combined with immune-checkpoint inhibiting antibody PD-1 [90].…”

Arginine Deiminase Induces Immunogenic Cell Death and Is Enhanced by N-acetylcysteine in Murine MC38 Colorectal Cancer Cells and MDA-MB-231 Human Breast Cancer Cells In Vitro

“…In the current study, we used an NAC concentration of no more than 20 mM; this concentration not only induced tumor cell death, but may also promote memory T cell proliferation. Recently, it was demonstrated that the ADI-PEG 20 enhances the response to anti-PD-1/PD-L1 in mouse models, with results suggesting a possible synergistic interaction [ 8 ]. Our current study shows that the efficacy of ADI-PEG 20 was enhanced in combination with NAC, suggesting that the combination of ADI-PEG 20, NAC, and anti-PD-1/PD-L1 blockade may be a promising therapeutic approach for the treatment of cancers.…”

Targeting Tumor Metabolism: A New Challenge to Improve Immunotherapy

“…Depletion of arginine was assessed using ADI-PEG20 inhibitor ( 157 ). It can inhibit cell proliferation in vitro and tumor growth in vivo and decrease Treg accumulation ( 158 ). However, it would be more pertinent to prevent amino acid depletion by tumor cells or myeloid cells rather than decreasing amino acid rates in the TME.…”