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

Alexandra Giatromanolaki; Adrian L Harris; Michael I Koukourakis

doi:10.1186/s40170-021-00264-7

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

Cancer Metab. 2021 Aug 3;9(1):28. doi: 10.1186/s40170-021-00264-7.

Authors

Alexandra Giatromanolaki^{1

2}, Adrian L Harris³, Michael I Koukourakis^{4

5}

Affiliations

¹ Department of Pathology, University Hospital of Alexandroupolis, Democritus University of Thrace, PO BOX 12, 68100, Alexandroupolis, Greece.
² Department of Radiotherapy/Oncology, University Hospital of Alexandroupolis, Democritus University of Thrace, PO BOX 12, 68100, Alexandroupolis, Greece.
³ Cancer Research UK, Molecular Oncology Laboratories, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK.
⁴ Department of Pathology, University Hospital of Alexandroupolis, Democritus University of Thrace, PO BOX 12, 68100, Alexandroupolis, Greece. targ@her.forthnet.gr.
⁵ Department of Radiotherapy/Oncology, University Hospital of Alexandroupolis, Democritus University of Thrace, PO BOX 12, 68100, Alexandroupolis, Greece. targ@her.forthnet.gr.

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.

Keywords: ARG2; ASS1; Angiogenesis; Arginase; Arginine; Argininosuccinate synthase; Lung cancer; TILs.