The prognostic and therapeutic implications of distinct patterns of argininosuccinate synthase 1 (ASS1) and arginase-2 (ARG2) expression by cancer cells and tumor stroma in non-small-cell lung cancer

Abstract

Background Arginine (Arg) is essential for cancer cell growth and also for the activation of T cells. Thus, therapies aiming to reduce Arg utilization by cancer may prove detrimental for the immune response. Methods We examined the expression of two major enzymes involved in arginine depletion and replenishment, namely arginase ARG2 and argininosuccinate synthase ASS1, respectively, in a series of 98 NSCLCs. Their association with immune infiltrates and the postoperative outcome were also studied. Results ARG2 was expressed mainly by cancer-associated fibroblasts (CAFs) (58/98 cases; 59.2%), while ASS1 by cancer cells (75/98 cases; 76.5%). ASS1 and ARG2 expression patterns were not related to hypoxia markers. Auxotrophy, implied by the lack of expression of ASS1 in cancer cells, was associated with high angiogenesis (p < 0.02). ASS1 expression by cancer cells was associated with a high density of iNOS-expressing tumor-infiltrating lymphocytes (iNOS+TILs). ARG2 expression by CAFs was inversely related to the TIL-density and linked with poorer prognosis (p = 0.02). Patients with ASS1 expression by cancer cells had a better prognosis especially when CAFs did not express ARG2 (p = 0.004). Conclusions ARG2 and ASS1 enzymes are extensively expressed in NSCLC stroma and cancer cells, respectively. Auxotrophic tumors have a poor prognosis, potentially by utilizing Arg, thus reducing Arg-dependent TIL anti-tumor activity. ASS1 expression in cancer cells would allow Arg fueling of iNOS+TILs and enhance anti-tumor immunity. However, upregulation of ARG2 in CAFs may divert Arg from TILs, allowing immune escape. Identification of these three distinct phenotypes may be useful in the individualization of Arg-targeting therapies and immunotherapy.

RETRACTED ARTICLE: N(6)-adenosine-methyltransferase-14 promotes glioma tumorigenesis by repressing argininosuccinate synthase 1 expression in an m6A-dependent manner

“…Argininosuccinate synthetase (ASS1) is located at 9q34 and is regarded as a vital step in the pathway of catalyzing arginine biosynthesis [ 17 ]. ASS1 is also abnormally expressed in many types of malignant tumors and is closely related to the occurrence and progression of tumors, including non-small cell lung cancer (NSCLC) [ 18 ], renal cell carcinoma (RCC) [ 19 ] and bladder cancer (BCa) [ 20 ]. However, the biological effects and molecular mechanisms in gliomas still need to be further explored.…”

OATD-02 Validates the Benefits of Pharmacological Inhibition of Arginase 1 and 2 in Cancer

“…Arginase biology has been studied in multiple contexts, resulting in the identification of ARG1 and ARG2 as therapeutic targets in cancer [ 18 , 44 , 45 , 46 ], as well as potential biomarkers for cancer progression [ 47 , 48 , 49 , 50 ]. Extensive research has provided strong evidence that dysregulated arginase activity accompanies various types of neoplastic diseases [ 51 ], and the inhibition of arginases contributes to the restoration of the effective immune response against cancer [ 4 , 5 , 15 , 24 , 42 , 52 ].…”

Argininosuccinate synthase 1, arginine deprivation therapy and cancer management

“…In non-small-cell lung cancer, lack of expression of ASS1 in tumor cells is associated with high angiogenesis. Patients with ASS1 expression in tumor cells exhibit a favorable prognosis, which may be related to high density of iNOS-expressing tumorinfiltrating lymphocytes in tumor cells with ASS1 expression (Giatromanolaki et al, 2021). ASS1 is lower in renal cell carcinomas compared with paired normal tissues, and a lower ASS1 expression is correlated with a worse prognosis in patients with renal cell carcinoma (Wang et al, 2019).…”

“…ASS1 is the enzyme that catalyzes the conversion of nitrogen from ammonia and aspartate from glutamine to form argininosuccinate. The somatic silence of ASS1 expression is commonly observed in a wide range of tumors, such as mesothelioma, non-small-cell lung cancer, myxofibrosarcomas (Huang et al, 2013;Szlosarek et al, 2017;Giatromanolaki et al, 2021). Moreover, low ASS1 expression levels in tumor tissues are associated with unfavorable clinical outcomes in a wide variety of malignancies.…”