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Innate and adaptive resistance mechanisms to arginine deprivation therapies in sarcoma and other cancers.

ABSTRACT: Many cancers lack functional expression of the enzyme argininosuccinate synthetase 1 (ASS1) that is necessary for synthesis of L-arginine. These cancers must import arginine for survival and growth, and this reliance can be targeted by arginine-degrading extracellular enzymatic drugs, most commonly PEGylated arginine deiminase. These enzymes can become targets of the immune system, reducing their effectiveness, but PEGylation improves the in vivo stability. Arginine deprivation causes cell death in some cancers, but others gain resistance by expressing ASS1 after a starvation response is induced. Other resistance mechanisms are possible and explored, but these have not been observed specifically in response to arginine deprivation. Future studies, especially focusing on the mechanisms of ASS1 upregulation and metabolic adaptations, may yield insights into preventing or taking advantage of resistance adaptations to make arginine deprivation therapy more effective.

SUBMITTER: Rogers LC

PROVIDER: S-EPMC8992531 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Innate and adaptive resistance mechanisms to arginine deprivation therapies in sarcoma and other cancers.

Rogers Leonard C LC Van Tine Brian A BA

Cancer drug resistance (Alhambra, Calif.) 20190919 3

Many cancers lack functional expression of the enzyme argininosuccinate synthetase 1 (ASS1) that is necessary for synthesis of L-arginine. These cancers must import arginine for survival and growth, and this reliance can be targeted by arginine-degrading extracellular enzymatic drugs, most commonly PEGylated arginine deiminase. These enzymes can become targets of the immune system, reducing their effectiveness, but PEGylation improves the <i>in vivo</i> stability. Arginine deprivation causes cel ...[more]

PMID: 35582579

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Project description:BACKGROUND:Prostate cancer (PCa), the second most common cancer affecting men worldwide, shows a broad spectrum of biological and clinical behaviour representing the epiphenomenon of an extreme heterogeneity. Androgen deprivation therapy is the mainstay of treatment for advanced forms but after few years the majority of patients progress to castration-resistant prostate cancer (CRPC), a lethal form that poses considerable therapeutic challenges. METHODS:Western blotting, immunocytochemistry, invasion and reporter assays, and in vivo studies were performed to characterize androgen resistant sublines phenotype in comparison to the parental cell line LNCaP. RNA microarray, mass spectrometry, integrative transcriptomic and proteomic differential analysis coupled with GeneOntology and multivariate analyses were applied to identify deregulated genes and proteins involved in CRPC evolution. RESULTS:Treating the androgen-responsive LNCaP cell line for over a year with 10 ?M bicalutamide both in the presence and absence of 0.1 nM 5-?-dihydrotestosterone (DHT) we obtained two cell sublines, designated PDB and MDB respectively, presenting several analogies with CRPC. Molecular and functional analyses of PDB and MDB, compared to the parental cell line, showed that both resistant cell lines were PSA low/negative with comparable levels of nuclear androgen receptor devoid of activity due to altered phosphorylation; cell growth and survival were dependent on AKT and p38MAPK activation and PARP-1 overexpression; their malignant phenotype increased both in vitro and in vivo. Performing bioinformatic analyses we highlighted biological processes related to environmental and stress adaptation supporting cell survival and growth. We identified 15 proteins that could direct androgen-resistance acquisition. Eleven out of these 15 proteins were closely related to biological processes involved in PCa progression. CONCLUSIONS:Our models suggest that environmental factors and epigenetic modulation can activate processes of phenotypic adaptation driving drug-resistance. The identified key proteins of these adaptive phenotypes could be eligible targets for innovative therapies as well as molecules of prognostic and predictive value.

Project description:BackgroundPediatric patients with recurrent/metastatic Ewing sarcoma (ES) have a dismal 5-year survival. Novel therapeutic approaches are desperately needed. Natural killer (NK) cell number and function are low in ES patient tumors, in large part due to the immunosuppressive tumor microenvironment (TME). Melanoma cell adhesion molecule (MCAM) is highly expressed on ES and associated with ES metastasis. NKTR-255 is a polymer-conjugated recombinant human interleukin-15 (IL-15) agonist improving NK cell activity and persistence. Magrolimab (MAG) is a CD47 blockade that reactivates the phagocytic activity of macrophages.MethodsTranscriptome profiling coupled with CIBERSORT analyses in both ES mouse xenografts and human patient tumors were performed to identify mechanisms of NK resistance in ES TME. A chimeric antigen receptor (CAR) NK cell targeting MCAM was engineered by CAR mRNA electroporation into ex vivo expanded NK cells. In vitro cytotoxicity assays were performed to investigate the efficacy of anti-MCAM-CAR-NK cell alone or combined with NKTR-255 against ES cells. Interferon-γ and perforin levels were measured by ELISA. The effect of MAG on macrophage phagocytosis of ES cells was evaluated by in vitro phagocytosis assays. Cell-based and patient-derived xenograft (PDX)-based xenograft mouse models of ES were used to investigate the antitumor efficacy of CAR-NK alone and combined with NKTR-255 and MAG in vivo.ResultsWe found that NK cell infiltration and activity were negatively regulated by tumor-associated macrophages (TAM) in ES TME. Expression of anti-MCAM CAR significantly and specifically enhanced NK cytotoxic activity against MCAMhigh but not MCAM-knockout ES cells in vitro, and significantly reduced lung metastasis and extended animal survival in vivo. NKTR-255 and MAG significantly enhanced in vitro CAR-NK cytotoxicity and macrophage phagocytic activity against ES cells, respectively. By combining with NKTR-255 and MAG, the anti-MCAM-CAR-NK cell significantly decreased primary tumor growth and prolonged animal survival in both cell- and PDX-based ES xenograft mouse models.ConclusionsOur preclinical studies demonstrate that immunotherapy via the innate immune system by combining tumor-targeting CAR-NK cells with an IL-15 agonist and a CD47 blockade is a promising novel therapeutic approach to targeting MCAMhigh malignant metastatic ES.

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Innate and adaptive resistance mechanisms to arginine deprivation therapies in sarcoma and other cancers.

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Innate and adaptive resistance mechanisms to arginine deprivation therapies in sarcoma and other cancers.

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