ARGINASE 1 IS A MARKER OF MYELOID-MEDIATED IMMUNOSUPPRESSION WITH PROGNOSTIC MEANING IN CLASSIC HODGKIN’S LYMPHOMA
(Abstract release date: 05/19/16)
EHA Library. ROMANO A. 06/09/16; 132933; E1384
Disclosure(s): No conflict of interest to declare
Dr. ALESSANDRA ROMANO
Contributions
Contributions
Abstract
Abstract: E1384
Type: Eposter Presentation
Background
The role of microenvironment in the pathogenesis of classic Hodgkin`s Lymphoma (HL) is well recognized. Our previous work showed that myeloid-derived suppressor cells have prognostic meaning, but their detection in peripheral blood is controversial due to lack of specific surface markers that could help to distinguish from mature polymorphonuclear neutrophils (PMN).
Aims
Evaluate if mature PMN in HL are different from healthy and in particular if they are immunosuppressive
Methods
Using oligonucleotide microarrays, we first evaluated the gene expression profile (GEP) of PMN at the steady state in 5 HL and 5 healthy subjects matched for sex and age, identifying arginase (Arg-1) among the first 10 genes differentially expressed in HL versus healthy PMN. Secondly, we investigated if HL-PMN could suppress T-cell activation. Thirdly, since we found that N-HL immunosuppression was due to the increased amount of Arginase-1, we prospectively measured Arginase (s-Arg-1) in sera collected from 118 HL patients, distinguished in a training set (N=40) and a validation set (N=78), and 35 healthy participants.
Results
Arg-1 was increased in HL-PMN (at both m-RNA and protein level), with an increased activity up to 15 times compared to healthy subjects matched for age and sex. In lymphocytes isolated from healthy subjects and PHA-activated, T-cell proliferation and expression of activation markers were down-regulated by co-culture of with HL-N at ratio 1:2, 1:4, and 1:8. s-Arg-1 was increased in HL patients compared to healthy subjects, and reduced after therapy. At diagnosis, s-Arg-1 was higher in patients with advanced stage (p=0.045), carrying B-symptoms (p=0.0048) and with a positive PET-2 scan after two cycles of chemotherapy (p=0.012).In the validation set, baseline levels of s-Arg-1 >200 ng/mL resulted in 92% sensitivity and 56% specificity to identify patients with positive PET-2 scan. Patients carrying s-Arg-1 more than 200 ng/mL had a shorter progression free survival. In multivariate analysis, PET-2 and s-Arg-1 at diagnosis were the only significant prognostic variables (respectively p=0.0004 and p=0.012).With these two prognostic variables, we were able to define three distinct groups based on PET-2 status after two cycles of chemotherapy and s-Arg-1 level at diagnosis. Patients with low s-Arg-1 and negative PET-2 scan (score 0, N=63) had 89.5% PFS at 36 months versus 67.6% of patients with at least one unfavourable prognostic factors (score 1, N=46) versus 37% of those patients with high s-Arg-1 and positive PET-2 (score 2, N=9, p=0.0004).
Conclusion
In HL, neutrophils are dysfunctional and immunosuppressive. They also produce Arg-1 that can be easily measured and represents a promising prognostic tool, to validate in larger prospective series.
Session topic: E-poster
Keyword(s): Hodgkin's disease, Myelosuppression, Prognostic factor
Type: Eposter Presentation
Background
The role of microenvironment in the pathogenesis of classic Hodgkin`s Lymphoma (HL) is well recognized. Our previous work showed that myeloid-derived suppressor cells have prognostic meaning, but their detection in peripheral blood is controversial due to lack of specific surface markers that could help to distinguish from mature polymorphonuclear neutrophils (PMN).
Aims
Evaluate if mature PMN in HL are different from healthy and in particular if they are immunosuppressive
Methods
Using oligonucleotide microarrays, we first evaluated the gene expression profile (GEP) of PMN at the steady state in 5 HL and 5 healthy subjects matched for sex and age, identifying arginase (Arg-1) among the first 10 genes differentially expressed in HL versus healthy PMN. Secondly, we investigated if HL-PMN could suppress T-cell activation. Thirdly, since we found that N-HL immunosuppression was due to the increased amount of Arginase-1, we prospectively measured Arginase (s-Arg-1) in sera collected from 118 HL patients, distinguished in a training set (N=40) and a validation set (N=78), and 35 healthy participants.
Results
Arg-1 was increased in HL-PMN (at both m-RNA and protein level), with an increased activity up to 15 times compared to healthy subjects matched for age and sex. In lymphocytes isolated from healthy subjects and PHA-activated, T-cell proliferation and expression of activation markers were down-regulated by co-culture of with HL-N at ratio 1:2, 1:4, and 1:8. s-Arg-1 was increased in HL patients compared to healthy subjects, and reduced after therapy. At diagnosis, s-Arg-1 was higher in patients with advanced stage (p=0.045), carrying B-symptoms (p=0.0048) and with a positive PET-2 scan after two cycles of chemotherapy (p=0.012).In the validation set, baseline levels of s-Arg-1 >200 ng/mL resulted in 92% sensitivity and 56% specificity to identify patients with positive PET-2 scan. Patients carrying s-Arg-1 more than 200 ng/mL had a shorter progression free survival. In multivariate analysis, PET-2 and s-Arg-1 at diagnosis were the only significant prognostic variables (respectively p=0.0004 and p=0.012).With these two prognostic variables, we were able to define three distinct groups based on PET-2 status after two cycles of chemotherapy and s-Arg-1 level at diagnosis. Patients with low s-Arg-1 and negative PET-2 scan (score 0, N=63) had 89.5% PFS at 36 months versus 67.6% of patients with at least one unfavourable prognostic factors (score 1, N=46) versus 37% of those patients with high s-Arg-1 and positive PET-2 (score 2, N=9, p=0.0004).
Conclusion
In HL, neutrophils are dysfunctional and immunosuppressive. They also produce Arg-1 that can be easily measured and represents a promising prognostic tool, to validate in larger prospective series.
Session topic: E-poster
Keyword(s): Hodgkin's disease, Myelosuppression, Prognostic factor
Abstract: E1384
Type: Eposter Presentation
Background
The role of microenvironment in the pathogenesis of classic Hodgkin`s Lymphoma (HL) is well recognized. Our previous work showed that myeloid-derived suppressor cells have prognostic meaning, but their detection in peripheral blood is controversial due to lack of specific surface markers that could help to distinguish from mature polymorphonuclear neutrophils (PMN).
Aims
Evaluate if mature PMN in HL are different from healthy and in particular if they are immunosuppressive
Methods
Using oligonucleotide microarrays, we first evaluated the gene expression profile (GEP) of PMN at the steady state in 5 HL and 5 healthy subjects matched for sex and age, identifying arginase (Arg-1) among the first 10 genes differentially expressed in HL versus healthy PMN. Secondly, we investigated if HL-PMN could suppress T-cell activation. Thirdly, since we found that N-HL immunosuppression was due to the increased amount of Arginase-1, we prospectively measured Arginase (s-Arg-1) in sera collected from 118 HL patients, distinguished in a training set (N=40) and a validation set (N=78), and 35 healthy participants.
Results
Arg-1 was increased in HL-PMN (at both m-RNA and protein level), with an increased activity up to 15 times compared to healthy subjects matched for age and sex. In lymphocytes isolated from healthy subjects and PHA-activated, T-cell proliferation and expression of activation markers were down-regulated by co-culture of with HL-N at ratio 1:2, 1:4, and 1:8. s-Arg-1 was increased in HL patients compared to healthy subjects, and reduced after therapy. At diagnosis, s-Arg-1 was higher in patients with advanced stage (p=0.045), carrying B-symptoms (p=0.0048) and with a positive PET-2 scan after two cycles of chemotherapy (p=0.012).In the validation set, baseline levels of s-Arg-1 >200 ng/mL resulted in 92% sensitivity and 56% specificity to identify patients with positive PET-2 scan. Patients carrying s-Arg-1 more than 200 ng/mL had a shorter progression free survival. In multivariate analysis, PET-2 and s-Arg-1 at diagnosis were the only significant prognostic variables (respectively p=0.0004 and p=0.012).With these two prognostic variables, we were able to define three distinct groups based on PET-2 status after two cycles of chemotherapy and s-Arg-1 level at diagnosis. Patients with low s-Arg-1 and negative PET-2 scan (score 0, N=63) had 89.5% PFS at 36 months versus 67.6% of patients with at least one unfavourable prognostic factors (score 1, N=46) versus 37% of those patients with high s-Arg-1 and positive PET-2 (score 2, N=9, p=0.0004).
Conclusion
In HL, neutrophils are dysfunctional and immunosuppressive. They also produce Arg-1 that can be easily measured and represents a promising prognostic tool, to validate in larger prospective series.
Session topic: E-poster
Keyword(s): Hodgkin's disease, Myelosuppression, Prognostic factor
Type: Eposter Presentation
Background
The role of microenvironment in the pathogenesis of classic Hodgkin`s Lymphoma (HL) is well recognized. Our previous work showed that myeloid-derived suppressor cells have prognostic meaning, but their detection in peripheral blood is controversial due to lack of specific surface markers that could help to distinguish from mature polymorphonuclear neutrophils (PMN).
Aims
Evaluate if mature PMN in HL are different from healthy and in particular if they are immunosuppressive
Methods
Using oligonucleotide microarrays, we first evaluated the gene expression profile (GEP) of PMN at the steady state in 5 HL and 5 healthy subjects matched for sex and age, identifying arginase (Arg-1) among the first 10 genes differentially expressed in HL versus healthy PMN. Secondly, we investigated if HL-PMN could suppress T-cell activation. Thirdly, since we found that N-HL immunosuppression was due to the increased amount of Arginase-1, we prospectively measured Arginase (s-Arg-1) in sera collected from 118 HL patients, distinguished in a training set (N=40) and a validation set (N=78), and 35 healthy participants.
Results
Arg-1 was increased in HL-PMN (at both m-RNA and protein level), with an increased activity up to 15 times compared to healthy subjects matched for age and sex. In lymphocytes isolated from healthy subjects and PHA-activated, T-cell proliferation and expression of activation markers were down-regulated by co-culture of with HL-N at ratio 1:2, 1:4, and 1:8. s-Arg-1 was increased in HL patients compared to healthy subjects, and reduced after therapy. At diagnosis, s-Arg-1 was higher in patients with advanced stage (p=0.045), carrying B-symptoms (p=0.0048) and with a positive PET-2 scan after two cycles of chemotherapy (p=0.012).In the validation set, baseline levels of s-Arg-1 >200 ng/mL resulted in 92% sensitivity and 56% specificity to identify patients with positive PET-2 scan. Patients carrying s-Arg-1 more than 200 ng/mL had a shorter progression free survival. In multivariate analysis, PET-2 and s-Arg-1 at diagnosis were the only significant prognostic variables (respectively p=0.0004 and p=0.012).With these two prognostic variables, we were able to define three distinct groups based on PET-2 status after two cycles of chemotherapy and s-Arg-1 level at diagnosis. Patients with low s-Arg-1 and negative PET-2 scan (score 0, N=63) had 89.5% PFS at 36 months versus 67.6% of patients with at least one unfavourable prognostic factors (score 1, N=46) versus 37% of those patients with high s-Arg-1 and positive PET-2 (score 2, N=9, p=0.0004).
Conclusion
In HL, neutrophils are dysfunctional and immunosuppressive. They also produce Arg-1 that can be easily measured and represents a promising prognostic tool, to validate in larger prospective series.
Session topic: E-poster
Keyword(s): Hodgkin's disease, Myelosuppression, Prognostic factor
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