Abstract
Purpose: Glioblastoma (GBM) is an incurable primary brain tumor that has not benefited from
immunotherapy to-date. Greater than 90% of GBM expresses the tryptophan (Trp) metabolic
enzyme, indoleamine 2,3-dioxygenase 1 (IDO). This observation supported the historical
hypothesis that IDO suppresses the antitumor immune response solely through a mechanism that
requires intratumoral Trp depletion. However, recent findings led us to investigate the alternative
hypothesis that IDO suppresses the anti-GBM immune response independent of its association
with Trp metabolism.
Experimental Design: IDO-deficient GBM cell lines reconstituted with IDO wild-type or IDO
enzyme-null cDNA were created and validated in vitro and in vivo. Microarray analysis was
conducted to search for genes that IDO regulates, followed by the analysis of human GBM cell
lines, patient GBM and plasma, and the TCGA database. Ex vivo cell co-culture assays,
syngeneic and humanized mouse GBM models were used to test the alternative hypothesis.
Results: Non-enzymic tumor cell IDO activity decreased the survival of experimental animals
and increased the expression of complement factor H (CFH) and its isoform, factor H like
protein 1 (FHL-1) in human GBM. Tumor cell IDO increased CFH and FHL-1 expression
independent of tryptophan metabolism. Increased intratumoral CFH and FHL-1 levels were
associated with poorer survival among glioma patients. Similar to IDO effects, GBM cell FHL-1
expression increased intratumoral Tregs and MDSCs while it decreased overall survival in mice
with GBM.
Conclusions: Our study reveals a newly non-metabolic IDO-mediated enhancement of CFH
expression and provides a new therapeutic target in patients with GBM.
immunotherapy to-date. Greater than 90% of GBM expresses the tryptophan (Trp) metabolic
enzyme, indoleamine 2,3-dioxygenase 1 (IDO). This observation supported the historical
hypothesis that IDO suppresses the antitumor immune response solely through a mechanism that
requires intratumoral Trp depletion. However, recent findings led us to investigate the alternative
hypothesis that IDO suppresses the anti-GBM immune response independent of its association
with Trp metabolism.
Experimental Design: IDO-deficient GBM cell lines reconstituted with IDO wild-type or IDO
enzyme-null cDNA were created and validated in vitro and in vivo. Microarray analysis was
conducted to search for genes that IDO regulates, followed by the analysis of human GBM cell
lines, patient GBM and plasma, and the TCGA database. Ex vivo cell co-culture assays,
syngeneic and humanized mouse GBM models were used to test the alternative hypothesis.
Results: Non-enzymic tumor cell IDO activity decreased the survival of experimental animals
and increased the expression of complement factor H (CFH) and its isoform, factor H like
protein 1 (FHL-1) in human GBM. Tumor cell IDO increased CFH and FHL-1 expression
independent of tryptophan metabolism. Increased intratumoral CFH and FHL-1 levels were
associated with poorer survival among glioma patients. Similar to IDO effects, GBM cell FHL-1
expression increased intratumoral Tregs and MDSCs while it decreased overall survival in mice
with GBM.
Conclusions: Our study reveals a newly non-metabolic IDO-mediated enhancement of CFH
expression and provides a new therapeutic target in patients with GBM.
| Original language | English |
|---|---|
| Journal | Clinical Cancer Research |
| DOIs | |
| Publication status | Published - 1 Dec 2021 |