Objective

In this project, I will attempt to address the following questions:
  1. What are Myeloid Derived Suppressor Cells (MDSCs) and how are they involved in cancer formation?
  2. Are MDSCs or their associated chemical pathways potential targets for chemotherapy or immunotherapy?







Introduction

This project falls largely into the realm of cancer immunology, which is the study of interactions between the immune system and cancer. In immunocompetent individuals, the immune system is capable of eliminating malignancies; however, in patients with malignant tumors, the immune system is highly suppressed, allowing the uncontrolled proliferation of tumor cells. Cancer immunotherapy attempts to treat cancer by stimulating the immune system to recognize and eliminate tumor cells in the body. To date, the field has largely been marked by failure and a fair amount of skepticism. (cite) However, I believe that this is one of the most promising fields of cancer treatment, especially after researching it in the context of Myeloid Derived Suppressor Cells (MDSC), which could potentially be a crucial protective system involved in rendering cancer unresponsive to innate and drug induced antitumor immunity.[1]


Myeloid Derived Suppressor Cells: Origin and Function

The presence of myeloid derived suppressor cells at increased levels in cancer patients has been known for at least two decades, however, it was not until recently that their true importance has begun to surface. MDSCs are a heterogeneous mixture of immature myeloid cells, which are functionally similar in that they suppress the immune system in the presence of cancer and a number of other diseases. [2] [3] In humans, known MDSC phenotypes include the following: CD11b+, Gr-1+, F4/80int, CD11clow, MHCII−/low, Ly-6C+, ER-MP58+ and CD31+. In addition, cells of the same phenotype have been documented at increased levels in patients with varying pathologies, including infections such as trypanosomiasis and salmonellosis,[4] indicating their crucial role in immune regulation.

Normally, common myeloid progenitor (CMP) cells in the bone marrow differentiate and give rise to immature myeloid cells (IMCs), which subsequently mature into functionally specialized innate immune cells such as macrophages and dendritic cells (DCs) based on a complex network of intercellular signaling pathways. MDSC are IMCs that have diverged from the normal path of development and kept their immature myeloid characteristics, but gained suppressive phenotypes.[5]

MDSC divergence from normal IMC development path in the presence of malignancies. from: Myeloid-derived suppressor cell role in tumor-related inflammation http://0-www.sciencedirect.com.sculib.scu.edu/science/article/pii/S0304383508002036#section0010
MDSC divergence from normal IMC development path in the presence of malignancies. from: Myeloid-derived suppressor cell role in tumor-related inflammation http://0-www.sciencedirect.com.sculib.scu.edu/science/article/pii/S0304383508002036#section0010
Under normal conditions, MDSC expression is maintained at very low levels in humans. On average, a normal individual maintains a population of cells expressing MDSC phenotypes which comprises about 2-3% of peripheral blood mononuclear cells. In cancer patients, MDSC expression in the blood was found to be 10 times normal levels on average[6] and at extremely high concentrations in the tumor environment. In addition, multiple experiments in mice have shown that, in the presence of a tumor, MDSC levels markedly increase in the spleen, blood, lungs, and liver. Normally, the existence of immature myeloid cells expressing phenotypes of MDSC is temporary and has been indicated as a regulatory factor of the immune system designed to avoid damage caused by chronic inflammation and damaging auto-immune responses.[7] [8]


MDSCs and Cancer

Inhibition of Antitumor Immune Function:

The most notable action of MDSC in relation to cancer is the inhibition of antitumor immunity. CD8+ cytotoxic T-lymphocytes are the main target of suppression by MDSC, which exhibit multiple methods of inhibition on these cells, highlighting the phenotypic diversity yet functional similarity of MDSCs.[9] Firstly, MDSC have an an increased level of metabolism of L-arginine through expression of the enzymes arginase and Nitrous Oxide Synthase (NOS), both of which are arginine dependent enzymes. Arginine depletion has been documented to have a dramatic effect on T-Cell differentiation, activation, and function.[10] Shortage of arginine causes loss of T-cell receptor signaling (which is arginine dependent) and cell cycle arrest in the G0 stage, thus producing T-cell tolerance to tumor specific antigens (TSA) and reduced populations of functional T-cells. NOS, which is also heavily overexpressed in MDSC, produces Nitrous Oxide (NO), which has been shown to be involved in inducing apoptosis in T-cells under close proximity contact with MDSC.[11]

immuno-suppressive activity of MDSC. from: "Cross-Talk between Myeloid-Derived Suppressor Cells and Macrophages Subverts Tumor Immunity toward a Type 2 Response" http://www.jimmunol.org/content/179/2/977/F7.expansion.html
immuno-suppressive activity of MDSC. from: "Cross-Talk between Myeloid-Derived Suppressor Cells and Macrophages Subverts Tumor Immunity toward a Type 2 Response" http://www.jimmunol.org/content/179/2/977/F7.expansion.html

In addition to CD8+ inhibition, it was recently found that MDSC may also be involved in inhibition of innate natural killer (NK) cells. MHC class 1 molecules display antigens on all cell surfaces throughout the body, which are generated through degradation of proteins within the cell and used to distinguish healthy from defective cells. NK cells have the ability to recognize and eliminate malignant or defective cells without prior activation by recognizing under-expressed or absent levels of MHC class 1 molecules, which is a common trait in virus infected cells and cancer.[12] MDSC suppress macrophage expression of interleukin-12 (IL-12), which normally acts to stimulate NK cell activity, while simultaneously over-expressing IL-10, which suppresses normal maturation of dendritic cells (DC). DC are involved in recognition of foreign antigens and the subsequent presentation of those antigens to other immune cells in order to stimulate the adaptive immune response.[13] Thus, MDSC directly and indirectly inhibit several aspects of the immune system. The wide range of immune-inhibitory functions present in MDSC both speaks to the importance of these cells in ensuring the survival of a tumor, and also point to the possibility of MDSC as a target for therapy due to the invaluable role they seem to play as cancer's all-around defense against the immune system.

Promotion of Angiogenesis:

In addition to their immune-inhibitory functions, MDSC are known to promote angiogenesis, further contributing to promotion of tumor growth. MDSC express a variety of growth factors and regulatory citokines which stimulate angiogenesis. Among others, vascular endothelial growth factor (VEGF), platlet derived growth factor (PDGF), and basic fibroblast growth factor (bFGF) are important factors in promoting angiogenesis and tissue remodeling, and are found to be expressed by MDSC.[14] In addition, they have been found to express high levels of MMP-9 which increases bioavailability of VEGF. MDSC have also been shown to assist in angiogenesis by incorporating directly in the endothelium, acting as a sort of building block. While they this capability has been documented, it would appear that MDSC are minimally involved in this process.[15]


MDSCs as Targets in Immunotherapy


The idea of cancer vaccines represents the ideal form of cancer treatment. It is now well established that tumors display "danger signals" including tumor specific antigens (TSA) and that the immune system has the ability to recognize and eliminate malignant cells displaying these signs of dysfunction. The treatment would be highly specific in that, by nature, it would only affect cancer cells. Through stimulation of antitumor immunity by sensitizing the immune system to TSA, cancer vaccines could in theory completely eliminate a tumor mass with minimal side effects to a patient, if any.[16] [17]

However, even the best theory can run across unanticipated roadblocks on the path to practical application. Such is the case with cancer vaccines. Until very recently, the field of cancer immunotherapy, and in particular cancer vaccines, has been plagued by lack of success. Despite best efforts to stimulate an immune response, there seems to be an aspect of the disease that has yet to be targeted which bestows upon cancer extremely effective protection against the immune system. Given recent discoveries surrounding the function and involvement of MDSC in cancer promotion and immune evasion, it has been proposed that these cells are the key to essentially stripping a tumor of its support network and defenses, thereby limiting its growth potential and opening the door for cancer vaccines to become a viable treatment option. [18] As this connection becomes increasingly apparent, there has been a corresponding increase in the search for potential treatments to modulate MDSC activity.

Modulation/Inhibition of MDSC Activity:

Inhibition of MDSC activity has a potential two-fold benefit. Directly, limiting MDSC levels will reduce the tumor promoting effects of these cells, hopefully slowing tumor growth and deterring angiogenesis and metastasis. Indirectly, the absence of MDSC may decrease immune tolerance and increase the susceptibility of a tumor to immune attack. One problem which instantly presents itself to this approach is the fact that inhibition of MDSC is likely to result in inhibition of other immune cells as well, which would greatly diminish the viability of such a drug.[19] However, results seem positive so far. Recently, multiple studies have shown that specific modulation of MDSC activity is feasible, and that this action alone can improve survival, reduce rates of metastasis, and decrease the growth rate of tumors.

For instance, an early indicator that MDSC inhibition could have practical application can be found in a 2005 study published in Clinical Cancer Research which assessed the ability of gemcitibine to modulate MDSC activity and the subsequent effects on tumor-bearing mice. The study began by measuring suppressive activity in tumor bearing mice with gemcitibine compared to the control with under no treatment. Significantly, it was found that gemcitibine selectively inhibited MDSC in tumor-bearing mice, while having no effect on other populations of immune cells, namely macrophages, CD4+ and CD8+ T-cells, B-cells, and NK cells. In addition, it was shown in the same study that when gemcitibine is combined with Ad.IFN-β, which activates NK cells, lytic activity of NK cells was significantly enhanced when compared to either treatment administered alone.[20] Although this is a preliminary study, these result demonstrate the effectiveness of MDSC modulation and confirms that inhibition of MDSC can enhance efficacy of immunotherapy solutions.

Another success in modulation of MDSC comes in the form of a recent study published in International Immunopharmacology which shows that a chemical called Icariin (ICA), and more so its derivative ICT, have broad inhibitory properties in respect to MDSC. The exact mechanism of inhibition is not known, but the results of the study are promising. In an earlier study, the researchers found that these chemicals have elevated anti-inflammatory effects in humans, indicating their involvement in immune regulation. In the following study mentioned above, the authors definitively show that ICA and ICT act strongly on multiple variables associated with MDSC activity including overall number of MDSC, expression of specific cytokines, and overall tumor volume after treatment with ICA or ICT. There are two striking points of this study which are worth highlighting. First, It was found that ICA, and in particular ICT, nearly completely suppressed NO production,[21] which is known to be a hallmark of MDSC presence and crucial to their T-cell suppressing functions.[22] Secondly, mice treated with ICA and ICT showed dramatically lower tumor volume over time when compared to the control. Thus, these chemicals have potential for application as a potent inhibitor of MDSC activity, especially NO mediated T-cell inhibition, making them ideal for application in cancer treatment.

All-trans retinoic acid (ATRA) has also been shown to act as a potent modulator of MDSC expression in mice and humans. This chemical is already well known for its effectiveness in treating acute promyelocytic leukemia (APL).[23] The success of this chemical in treating APL arises from its ability to stimulate the differentiation of IMC into mature innate immune cells. while this effect is well documented in APL, it has recently been shown affect MDSC differentiation as well, giving it potential as a drug to reduce overall MDSC numbers by inducing their differentiation.[24]

in addition, a novel combination of MSDC suppression (in the form of gemcitibine) and Immune activation was presented by researchers in a 2007 study, and shows some of the most promising research to date. The experiment, published in the American Association for Cancer Research Journal, treated tumor bearing mice with various combinations of immune stimulating chemicals, including sensitizing the immune system to HER-2/neu surface antigen commonly overexpressed in multiple tumor types, particularly breast cancer. These treatments induced anti-tumor immunity with slight success, but not at a practically applicable level. However, when the experimenters implemented gemcitibine treatment in addition to the immune activating drugs, a strong anti-tumor response was induced. In addition, if treatment was administered earlier in the progression of the tumor, complete elimination of the tumor could be achieved using the combined approach.[25]

Tumor size over time under treatment with varying regimens of immune activating agents and gemcitibine. from: "A Combination of Chemoimmunotherapies Can Efficiently Break Self-Tolerance and Induce Antitumor Immunity in a Tolerogenic Murine Tumor Model" http://cancerres.aacrjournals.org/content/67/15/7477.long
Tumor size over time under treatment with varying regimens of immune activating agents and gemcitibine. from: "A Combination of Chemoimmunotherapies Can Efficiently Break Self-Tolerance and Induce Antitumor Immunity in a Tolerogenic Murine Tumor Model" http://cancerres.aacrjournals.org/content/67/15/7477.long


The results of this experiment clearly demonstrate the significance of MDSC as cancer promoters and inhibitors of anti-tumor immunity mediated by CTLs. When combined, it is evident that immunotherapy and inhibition of MDSC shows formidable potential to produce tumor regression effectively and with minimal host side effects.


Analysis/Conclusion

Currently, the field of Cancer immunotherapy has few practical applications. Despite the ability of the immune system to recognize and eliminate malignancies in immunocompetent individuals, cancer clearly has the ability to locally suppress immune function and induce immune tolerance in the tumor environment. Surpassing tumor immune suppression is becoming an increasingly prevalent issue as our understanding of cancer immunology increases. With the relatively recent influx discoveries concerning MDSC, it is becoming increasingly clear that these cells play a crucial role in this issue.

The data in the experiments presented above strongly support the possibility that MDSC modulation could become a key component in the success of immunotherapy solutions. In particular, the experiment involving HER-2/neu sensitization is especially poignant. The study supports the notion that inducing an anti-tumor response is indeed possible. Sensitization of the immune system to this tumor surface antigen alone was found to produce a mild but not significant anti-tumor response. However, it is the results concerning the gemcitibine and HER-2/neu combination which are the most significant. When combined with modulation of MDSC by gemcitibine, the efficacy of the counterpart immunotherapy solution skyrocketed in comparison, even resulting in complete remission in some cases.

An article published by Science in 2008 asserts: "MDSC are extremely versatile immune suppressors and clearly a force be reckoned with if immunotherapy is to succeed".[26] I would tend to agree. The data strongly suggest that MDSC are crucial players in cancer's defense and progression. These cells are perhaps not viable as a treatment target alone, but from the evidence, it is clear that researching methods of MDSC modulation is key to the success of future immunotherapy solutions. Cancer is commonly referred to as a "resilient" and "clever" disease capable of devising escape routes out of trouble seemingly with ease. This idea, although descriptively inaccurate in its association of intelligence to a disease, exemplifies the complex nature of cancer and of the underlying molecular mechanisms stimulating its growth and survival. Thus, it would not be surprising if MDSC activity was one of many main players involved with immune suppression. That said, These cells at the very least represent a move towards success and practical application of immunotherapy in the realm of cancer treatment.


References


  1. ^ Cancer's Bulwark Against Immune Attack: MDS cells
    http://0-www.sciencemag.org.sculib.scu.edu/content/319/5860/154.full.pdf?sid=026043f5-e8d2-4933-a7c4-c792813fea4e
  2. ^ Myeloid-derived-suppressor cells as regulators of the immune system
    http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2828349/
  3. ^ Cross-Talk between Myeloid-Derived Suppressor Cells and Macrophages Subverts Tumor Immunity toward a Type 2 Response
    http://www.jimmunol.org/content/179/2/977.long
  4. ^ Myeloid-derived suppressor cell role in tumor-related inflammation
    http://0-www.sciencedirect.com.sculib.scu.edu/science/article/pii/S0304383508002036#section0010
  5. ^ Myeloid-derived-suppressor cells as regulators of the immune system
    http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2828349/
  6. ^ Myeloid-derived-suppressor cells as regulators of the immune system
    http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2828349/
  7. ^ Myeloid-derived suppressor cell role in tumor-related inflammation
    http://0-www.sciencedirect.com.sculib.scu.edu/science/article/pii/S0304383508002036#section0010
  8. ^ Increased production of immature myeloid cells in cancer patients: a mechanism of immunosuppression in cancer.

    http://www.ncbi.nlm.nih.gov/pubmed/11123353

  9. ^ Myeloid-derived suppressor cell role in tumor-related inflammation
    http://0-www.sciencedirect.com.sculib.scu.edu/science/article/pii/S0304383508002036#section0010
  10. ^ Myeloid-derived-suppressor cells as regulators of the immune system
    http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2828349/
  11. ^ Arginase, Prostaglandins, and Myeloid-Derived Suppressor Cells in Renal Cell Carcinoma
    http://clincancerres.aacrjournals.org/content/13/2/721s.long
  12. ^ NK Cells and Cancer
    http://www.jimmunol.org/content/178/7/4011.full
  13. ^ Cross-Talk between Myeloid-Derived Suppressor Cells and Macrophages Subverts Tumor Immunity toward a Type 2 Response
    http://www.jimmunol.org/content/179/2/977.long#R16
  14. ^ Myeloid-derived suppressor cell role in tumor-related inflammation
    http://0-www.sciencedirect.com.sculib.scu.edu/science/article/pii/S0304383508002036#section0010
  15. ^ Role of haematopoietic cells and endothelial progenitors in tumour angiogenesis
    http://0-www.sciencedirect.com.sculib.scu.edu/science?_ob=MiamiImageURL&_imagekey=B6T23-4K8NWVW-1-1&_cdi=4907&_user=2665692&_pii=S0304419X06000345&_check=y&_origin=&_coverDate=08%2F31%2F2006&view=c&wchp=dGLbVlW-zSkWl&md5=77f2a08c83ab7a565e34fc61fc121e2b&ie=/sdarticle.pdf
  16. ^ The American Cancer Society website: "cancer vaccines"
    http://www.cancer.org/Treatment/TreatmentsandSideEffects/TreatmentTypes/Immunotherapy/immunotherapy-cancer-vaccines
  17. ^ Cancer Immunoediting: Integrating Immunity’s Roles in Cancer Suppression and Promotion
    http://www.sciencemag.org/content/331/6024/1565.full
  18. ^ Cancer's Bulwark Against Immune Attack: MDS cells
    http://0-www.sciencemag.org.sculib.scu.edu/content/319/5860/154.full.pdf?sid=026043f5-e8d2-4933-a7c4-c792813fea4e
  19. ^ Gemcitabine Selectively Eliminates Splenic Gr-1+/CD11b+ Myeloid Suppressor Cells in Tumor-Bearing Animals and Enhances Antitumor Immune Activity
    http://clincancerres.aacrjournals.org/content/11/18/6713.long
  20. ^ Gemcitabine Selectively Eliminates Splenic Gr-1+/CD11b+ Myeloid Suppressor Cells in Tumor-Bearing Animals and Enhances Antitumor Immune Activity
    http://clincancerres.aacrjournals.org/content/11/18/6713.long
  21. ^ Icariin and its derivative, ICT, exert anti-inflammatory, anti-tumor effects, and modulate myeloid derived suppressive cells (MDSCs) functions
    http://0-www.sciencedirect.com.sculib.scu.edu/science?_ob=MImg&_imagekey=B6W7N-51YGMKT-1-1&_cdi=6631&_user=2665692&_pii=S1567576911000270&_origin=search&_coverDate=01%2F15%2F2011&_sk=999999999&view=c&wchp=dGLbVtz-zSkzk&md5=6d8839b4aa037901001f9ace996e44a1&ie=/sdarticle.pdf
  22. ^ Myeloid-derived-suppressor cells as regulators of the immune system
    http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2828349/
  23. ^ All-trans retinoic acid in acute promyelocytic leukemia: long-term outcome and prognostic factor analysis from the North American Intergroup protocol
    http://bloodjournal.hematologylibrary.org/content/100/13/4298.full.html
  24. ^ Increased Production of Immature Myeloid Cells in Cancer Patients: A Mechanism of Immunosuppression in Cancer
    http://www.jimmunol.org/content/166/1/678.long
  25. ^ A Combination of Chemoimmunotherapies Can Efficiently Break Self-Tolerance and Induce Antitumor Immunity in a Tolerogenic Murine Tumor Model http://cancerres.aacrjournals.org/content/67/15/7477.long
  26. ^ Cancer's Bulwark Against Immune Attack:MDS cells
    http://0-www.sciencemag.org.sculib.scu.edu/content/319/5860/154.full.pdf?sid=026043f5-e8d2-4933-a7c4-c792813fea4e