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There is no specific marker to evaluate the immuno-suppressive status of cancer patients. Several markers, such as CD124, latency-associated peptide (LAP), arginase I, indole-amine-2,3-dioxygenase (IDO) and inducible nitric oxide synthase (iNOS), are known to be associated with immune suppression. However, there is little research regarding the change in these parameters after chemotherapy. The present study enrolled 23 chemo-naïve non-small cell lung cancer (NSCLC) patients and 19 healthy donors. From the 23 NSCLC patients, 11 post-chemotherapy samples were collected. Surface and functional markers were analyzed by flow-cytometry. The mean fluorescence intensities (MFI) of iNOS were higher and the MFI of LAP were lower in NSCLC patient than in healthy donors (P < 0.05). In a comparison of pre-chemotherapy and post-chemotherapy groups with NSCLC, the MFI of iNOS on granulocytes and monocytes and IDO on monocytes were significantly lower in the post-chemotherapy group than in the pre-chemotherapy group (P < 0.05). In a serial analysis with 10 patients who had paired samples and who showed clinical benefits from chemotherapy, the MFI of iNOS for both cell types, and of IDO and CD124 for monocytes decreased significantly after chemotherapy, compared with those before chemotherapy (iNOS, 4.79 ± 1.75 vs 2.83 ± 0.77, P = 0.005, for granulocytes and 6.15 ± 2.94 vs 2.76 ± 1.05, P = 0.005 for monocytes; IDO, 6.81 ± 3.43 vs 4.64 ± 1.55, P = 0.012 for monocytes; CD124, 2.31 ± 0.39 vs 1.94 ± 0.43, P = 0.008 for monocytes). The changes in arginase I and LAP expression were not significant. The changes in iNOS, IDO and CD124 expression were significant after chemotherapy in NSCLC. Further evaluation of the possibility of immune status monitoring using these parameters is needed. (Cancer Sci 2012; 103: 155–160)
The role of the immune system in tumor occurrence, progression and inhibition has been debated for many years. Swann et al. (2007) has revealed that tumor cells can escape the immune reaction by various means; one of these is immune suppression, which could depend on various tumor and host factors, including tumor-induced immune suppressor cells.(1)
One of these cells is known as the myeloid-derived suppressor cell (MDSC). Human MDSC phenotypes have not been clearly established, although MDSC phenotypes have been established in mice models.(2) Currently, human MDSC is regarded as a heterogeneous group having various morphological or functional phenotypes.(3) In cancer patients, MDSC can be found in tumor tissues, lymph nodes, in the spleen and in peripheral blood.(4,5) It has been reported that removal of cancer results in a decreased number of MDSC and that the reduction in MDSC improves the immune response in various cancer models.(3,6–8)
These cells adopt various means of suppressing the function of effector lymphocytes against tumor cells. Some studies suggest that several enzymes, such as arginase I (ARGI), indoleamine 2,3-dioxygenase (IDO) and inducible nitric oxide synthase (iNOS), as well as surface markers, such as latency associated peptide (LAP) and CD124, are related to immune suppression and tumor progression.(2,3,9–11) However, although these markers are known to be associated with immune suppressive cells and the presence of tumors, few have been investigated with regard to changes in these parameters after chemotherapy. Here, we investigate the differences in immune parameters between healthy people and advanced non-small cell lung cancer (NSCLC) patients. We also evaluate the change in these parameters after chemotherapy, which might be associated with the immune suppressive cells in advanced NSCLC patients.
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- Patients and Methods
- Disclosure Statement
The results of this study showed that there were significant differences and changes in several parameters, iNOS, IDO and CD124, which were associated with MDSC between advanced NSCLC patients and healthy donors and between pre-chemotherapy and post-chemotherapy status.
Altered immune status plays an important role in the development of cancer, and most patients with advanced cancer are immune-suppressed.(1) Studies have shown that various cells are involved in tumor-induced immune suppression. Among the various cells, MDSC are considered to be the major culprit in immune perturbation, as they are known to be associated with innate and adaptive immunity inhibition.(13)
Although many trials have sought to activate patients’ immune function against cancer, no effective result has emerged so far.(13) For effective immune activation against cancer, it is necessary to attenuate immune suppression and to monitor the extent of suppression.
In a laboratory model, MDSC are known to be a heterogeneous population. However, MDSC can be classified as either granulocytic or monocytic.(14,15) The role of the two MDSC subsets is not clear, but it has been reported that granulocytic MDSC requires close cell-to-cell contact with T cells in the lymphoid organ and that monocytic MDSC suppresses the immune reaction by producing various cytokines without direct cell-to-cell contact.(3) In our study, all of the immune parameters were measured in the peripheral blood. This explains the high expression of several markers, including IDO and CD 124 for monocytes.
The surface markers of MDSC have not been defined clearly in the human model. However, recent studies have suggested several surface or functional markers. CD124 (IL-4Rα) expression is a known surface marker of MDSC that is associated with producing transforming growth factor (TGF)-β via IL-13 stimulation from natural killer T cells.(16) LAP expression cells are also known to be associated with immune suppressive function through TGF-β.(11) Moreover, iNOS, ARG and IDO are well-known functional markers of MDSC, which suppress the immune function by producing reactive oxygen species and depleting arginine or tryptophan.(8,17) In our study, there was lower expression of iNOS, IDO and CD124 in the post-chemotherapy than in the pre-chemotherapy samples.
This might be associated with the immune suppressive status of the patients. Most of the responses to the treatment were SD or PR. Although there was no definite change in the size of lesions as a result of chemotherapy, these patients obtained a clinical benefit from the treatment. The decreased tumor burden might have improved the immune status. Another hypothesis is that immune suppressor cells are reduced by chemotherapy. This can alter the immune status. As a result, the immune parameters might change. This might be an implication of the improved immune status after chemotherapy.
Dendritic cells with high LAP expression rates have been reported to have immune an suppressive function.(11) In our study, LAP expression on myeloid cells was lower in cancer patients than in healthy donors. Furthermore, LAP expression has a tendency to increase after chemotherapy.
Immune functions of the patients are influenced by various factors (e.g. age, gender and smoking status) in addition to tumor status. Our observation is focused mainly on changes in MDSC-related markers with anti-cancer chemotherapy. Interpretation of the results is limited by the fact that other confounding variables can influence the immune parameters. Thus, further study with a large number of cancer patient samples is warranted.
This study has several limitations. First, this study did not involve a comparison of the changes in the immune parameters between the partial response or stable disease group and the progressive disease group. Therefore, it is not clear whether these changes were caused by the clinical benefits from chemotherapy. Second, the immune parameters were evaluated in peripheral blood, which does not reflect the local immune status around the tumor.
However, there have been few studies regarding the presence of MDSC and its relationship with cancer in humans.(18–21) Moreover, most of the data concerns the correlation between cancer and MDSC counts in cross-sectional analyses. Our study showed serial changes in various markers which were associated with MDSC for both pre-chemotherapy and post-chemotherapy conditions. This suggests the possibility of immune status monitoring using immune parameters that are associated with MDSC.
One recent report notes a change in the MDSC count after surgical treatment in NSCLC patients.(22) In that study, a specific subpopulation of mononuclear cells decreased after surgical removal of the tumor. This also suggests that specific cell subpopulations associated with MDSC are correlated with tumor burden.
In summary, several markers associated with MDSC showed significant differences between NSCLC patients and healthy donors. In a serial analysis between pre-chemotherapy and post-chemotherapy results, iNOS, IDO and CD124 expression decreased significantly after chemotherapy. Further study on the usefulness of monitoring these markers is warranted.