Kynurenine and 3-hydroxykynurenine, the products of IDO activity, exert also immunosuppressive functions, inhibiting effector T cell survival and proliferation Kynurenine was also reported to dampen NK cell function and proliferation In particular, MDSC produce large amounts of matrix metalloproteinases MMP , especially MMP9, which process the extracellular matrix and basal membrane and enable the tumor to leave the tissue, to enter the blood stream, and migrate to the site of later metastasis It was shown that the pre-metastatic niche is performed before the tumor cells enter the blood stream This process is still not fully understood but studies have confirmed that MDSC play an essential role 9 , It was found that MDSC accumulated in pre-metastatic niches with the help of monocyte chemoattractant protein-1 that dampens the activity of NK cells, which are also preferably found in the pre-metastatic niche In addition, it was reported that MDSC produce MMP9 within the pre-metastatic niche, facilitating the penetration of metastatic cells A further hallmark of tumor progression is angiogenesis that is crucial for the nutrition, vasculature, and dissemination of the tumor It was reported that blocking of angiogenesis resulted in the inhibition of tumor migration and formation of metastasis The expansion of MDSC has been demonstrated in many types of human tumors 6 , 7.
Moreover, elevated levels of MDSC were found not only in solid tumors but also in blood of non-Hodgkin lymphoma and multiple myeloma patients Importantly, the frequency of circulating MDSC was found to correlate with the disease stage. It was reported that patients with stage III and IV hepatocellular carcinoma, melanoma, non-small cell lung cancer, pancreatic, esophageal, gastric, and bladder cancer had higher frequencies of MDSC in the peripheral blood as compared to stage I and II patients 60 — In addition, an association between MDSC numbers and clinical response to radio-, chemo-, and immunotherapy was reported Several recent studies described that in melanoma patients treated with the immune checkpoint inhibitor, ipilimumab, decreased amounts and immunosuppressive functionality of both M- and PMN-MDSC correlated with beneficial therapeutic effects 65 — Altogether, these studies show that MDSC could be not only promising biomarkers for the survival of patients and the treatment efficacy but also could serve as a valuable target in combined immunotherapy of cancer patients.
In recent years, increasing numbers of preclinical and clinical studies were performed to target MDSC with beneficial effects, resulting in the tumor growth inhibition and the survival prolongation.
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Ongoing clinical trials are summarized in Table 1. Figure 2. Strategies for myeloid-derived suppressor cells MDSC targeting. Examples for each therapeutic approach are shown. Table 1.
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Ongoing clinical trials to target myeloid-derived suppressor cells MDSC in cancer patients. In preclinical mouse models, it has been demonstrated that inhibitors of phosphodiesterase-5, sildenafil, and tadalafil significantly inhibited the MDSC functions by the downregulation of iNOS and ARG1 activities, leading to the activation of antitumor immunity and the prolongation of survival of tumor-bearing mice 69 — Recent clinical trials with tadalafil in patients with head and neck squamous cell carcinoma and melanoma confirmed this positive effect 72 — It was shown that decreased amounts of MDSC and their immunosuppressive pattern correlated with an increased T cell reactivity and improved clinical outcome of advanced cancer patients.
A class I histone deacetylase inhibitor, entinostat, has been recently evaluated in several preclinical tumor models for its ability to affect MDSC functions 75 , In addition, they observed a strong reduction of tumor-infiltrating macrophages, suggesting a strong effect of this drug on the innate immunity. Interestingly, the combination of entinostat with anti-PD-1 antibodies significantly increased survival and delayed tumor growth in mice with LLC and renal cell carcinoma as compared to the treatment with anti-PD-1 antibodies alone.
A combined therapy with nivolumab and entinostat in renal cell carcinoma patients is now planned. A further promising way to target MDSC is the blockade of the activation of STAT3, which is a main transcription factor for immunosuppressive activity in myeloid cells In the past, a number of clinical trials have been performed to target STAT3 with small molecular inhibitors with a limited efficacy and broad side effects By this technique, a selective delivery of the drugs to TLR9-positive cells was ensured.
A further possibility to target MDSC is the modulation their metabolic pathways 81 , It was shown that tumor-infiltrating MDSC displayed an upregulation of the fatty acid translocase, CD36, which resulted in an increased uptake and oxidation of fatty acids. Pharmacological inhibition of the fatty acid oxidation decreased the immunosuppressive capacity of MDSC and in combination with low-dose chemotherapy and adoptive cellular therapy resulted in antitumor effect in LLC and colon adenocarcinoma mouse models Myeloid-derived suppressor cells exhibit their main immunosuppressive activity within the TME.
Therefore, intensive investigations were performed to block the migration of MDSC to the tumor site. Chemokine receptors are a key driving force for the migration of immune cells Interestingly, the patients with a mutated CCR5 variant were reported to be resistant to the prostate cancer development By targeting the CCR5-CCR5 ligand interaction, tumor growth and invasiveness could be suppressed in pancreatic, colorectal, prostate, and breast cancer 92 — All-trans retinoic acid ATRA seems to be a very promising agent for these approaches.
ATRA is a vitamin A derivative binding to the retinoic acid receptor.
Tumour-related immunosuppression and treating persistent bacterial infections
In a completed clinical trial, ATRA was applied in metastatic renal carcinoma patients in combination with the IL-2 administration In a second clinical trial with late stage small cell lung cancer patients, ATRA was used together with a DC vaccine against p53 It should be mentioned that ATRA was used in many other clinical trials with inhibitory effects on tumor progression; however, MDSC were not evaluated in these trials, and the positive effect was linked to other mechanisms.
Since tumor-derived EV were reported to induce the conversion of non-immunosuppressive IMC into MDSC and further activated their immunosuppressive functions 26 , 27 , the inhibitors of the EV release from tumor cells were tested in mice-bearing CT26 colon carcinoma It was demonstrated that the treatment of these mice with dimethyl amiloride or omeprazole reduced EV content in serum that was associated with the reduction of MDSC expansion and immunosuppressive activity Clinical trials with tyrosine kinase inhibitors such as sunitinib revealed that these agents could target MDSC.
Sunitinib treatment of metastatic renal cell carcinoma patients was reported to decrease the number of circulating MDSC , However, no significant prolongation of the overall survival was observed. Other chemotherapeutics such as gemcitabine and 5-fluorouracil were shown to induce selectively apoptosis of MDSC in the spleen and TME in several mouse tumor models — Interestingly, both chemotherapeutic agents displayed no significant effect on the frequencies of T cells, NK cells, DC, and B cells.
Similar to the preclinical observation, gemcitabine has no effect in effector T cells. An application of 5-fluorouracil in the preclinical mouse model and colorectal cancer patients affected MDSC, leading to the immune recovery and tumor regression Administration of another chemotherapeutic, docetaxel, induced a decrease of tumor burden in a preclinical mouse model of mammary carcinoma The effect of doxorubicin on MDSC in mammary cancer models was also investigated The treatment of these mice with doxorubicin led to the reduction of MDSC frequencies in the spleen, peripheral blood, and tumors.
Furthermore, the immunosuppressive activity of residual MDSC was impaired.
Study provides rationale for adding COX-2 inhibitors to improve anti-PD1 immunotherapy response
Moreover, this study demonstrated that MDSC isolated from patients were also sensitive to doxorubicin treatment in vitro Using Ret transgenic melanoma mouse model, we demonstrated that the administration of ultra-low, non-cytotoxic doses of paclitaxel induced the reduction of MDSC numbers and immunosuppressive functions Treated mice showed elevated activity of CD8 T cells, which correlated with the prolongation of mouse survival In addition, it was reported that the treatment of MDSC in vitro with ultra-low concentrations of paclitaxel stimulated their differentiation into DC Tumor cells developed multiple mechanisms to evade the immune system and to progress.
By altering MDSC function and biology, various preclinical and clinical studies showed a beneficial effect. This suggests that MDSC targeting could be a promising strategy to apply together with existing immunotherapeutic strategies such as boosting the immune system by vaccination or negative immune checkpoint inhibitors.
Thus, combining gemcitabine with a DNA vaccination induced a strong antitumor immune response accompanied by a reduced self-tolerance in a preclinical HER2-expressing mouse tumor model In addition, a clinical trial was initiated in stage IV melanoma patients, by whom ATRA was applied together with ipilimumab This trial and many other starting combinatorial approaches will help to develop an efficient strategy for the treatment of cancer patients.
VF: writing, review, and revision of the manuscript and revision of the figures. XH: preparing the figures. VN: preparing the table. CG: revision of the manuscript. VU: writing, review, and revision of the manuscript and revision of the table and figures. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Ostrand-Rosenberg S. Immune surveillance: a balance between protumor and antitumor immunity. Curr Opin Genet Dev —8. Cancer Immunol Immunother — Umansky V, Sevko A.
The Critical Role of Hypoxia in Tumor-Mediated Immunosuppression
Tumor microenvironment and myeloid-derived suppressor cells. Cancer Microenviron — Immunological factors influencing clinical outcome in lung cancer patients after telomerase peptide vaccination. Cancer Res — Gabrilovich D, Nagaraj S. Myeloid-derived-suppressor cells as regulators of the immune system. Nat Rev Immunol — Gabrilovich D. Myeloid-derived suppressor cells. Cancer Immunol Res —8. Myeloid-derived suppressor cells: critical cells driving immune suppression in the tumor microenvironment. Adv Cancer Res — The nature of myeloid-derived suppressor cells in the tumor microenvironment.
Trends Immunol — Paving the road to tumor development and spreading: myeloid-derived suppressor cells are ruling the fate. Front Immunol Ostrand-Rosenberg S, Sinha P. Myeloid-derived suppressor cells: linking inflammation and cancer. Cite Citation. Permissions Icon Permissions. Abstract Although recent cancer immunotherapy strategies, including immune-checkpoint blockade i. Open in new tab Download slide. Search ADS.
TGF-beta1 in tumor microenvironments induces immunosuppression in the tumors and sentinel lymph nodes and promotes tumor progression. Spatiotemporal dynamics of intratumoral immune cells reveal the immune landscape in human cancer. Functional network pipeline reveals genetic determinants associated with in situ lymphocyte proliferation and survival of cancer patients. Tumor-specific immunological recognition of frameshift-mutated peptides in colon cancer with microsatellite instability. Molecular and genetic properties of tumors associated with local immune cytolytic activity.
Cloning of the gene coding for a shared human melanoma antigen recognized by autologous T cells infiltrating into tumor. A mutated beta-catenin gene encodes a melanoma-specific antigen recognized by tumor infiltrating lymphocytes. Clonal neoantigens elicit T cell immunoreactivity and sensitivity to immune checkpoint blockade. Cancer metastasis is accelerated through immunosuppression during Snail-induced EMT of cancer cells.
Genomic and transcriptomic features of response to anti-PD-1 therapy in metastatic melanoma.
Complete regression of metastatic cervical cancer after treatment with human papillomavirus-targeted tumor-infiltrating T cells. Rethinking ovarian cancer II: reducing mortality from high-grade serous ovarian cancer.
Immunosuppression through constitutively activated NF-kappaB signalling in human ovarian cancer and its reversal by an NF-kappaB inhibitor. Role of the mitogen-activated protein kinase signaling pathway in the regulation of human melanocytic antigen expression. BRAF inhibitor vemurafenib improves the antitumor activity of adoptive cell immunotherapy. Selective BRAF inhibition decreases tumor-resident lymphocyte frequencies in a mouse model of human melanoma. The rapidly evolving therapies for advanced melanoma—towards immunotherapy, molecular targeted therapy, and beyond.
Enhanced cancer immunotherapy using STAT3-depleted dendritic cells with high Th1-inducing ability and resistance to cancer cell-derived inhibitory factors. Sunitinib mediates reversal of myeloid-derived suppressor cell accumulation in renal cell carcinoma patients.
Curotto de Lafaille. Beta-catenin stabilization extends regulatory T cell survival and induces anergy in nonregulatory T cells. Activation of beta-catenin in dendritic cells regulates immunity versus tolerance in the intestine. All rights reserved. For permissions, please e-mail: journals.
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