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.
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Authors | Alexandra Giatromanolaki, Adrian L Harris, Michael I Koukourakis |
Journal | Cancer & metabolism
(Cancer Metab)
Vol. 9
Issue 1
Pg. 28
(Aug 03 2021)
ISSN: 2049-3002 [Print] England |
PMID | 34344457
(Publication Type: Journal Article)
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Copyright | © 2021. The Author(s). |