Holistic Cancer Treatment: Low Dose Chemo – Part 7

In a galaxy far, far away…So scrolls the famous words of the Star Wars opening.  It is one of my favorite movies of all time. Thank you, George Lucas! If you haven’t seen this movie, the evil empire creates a Death Star with a surrounding force field that repeals any threat. The Death Star roams the galaxy, fomenting fear and destroying planets. Despite the impending doom, the rebels smuggle the plans, through a droid, to the resistance to then take down this force field to allow a targeted attack that destroys the Death Star. Hollywood does a great job telling a story and making it believable despite the inconceivable possibility of the story. Hollywood plays make-believe with our imaginations. I admit it is fun. Despite the far, far away reality of Star Wars, this fictitious scenario is evident in cancer’s reality. Of course, there is no Death Star in the body. But, how is the primary cancer tumor any different than a Death Star? The primary tumor mass is the Death Star within the galaxy that is the body. Likewise, there is no invisible force field within the body. However, cancer has a quasi invisible force field that repeals the resistance from targeting the destruction of the cancer Death Star. This repellant force field, in cancer that protects the cancer Death Star from targeted destruction by the resistance, is the suppression of the immune system within the tumor microenvironment. Of course, the resistance, or the rebellion in Star Wars, is the immune system.

I will discuss several of these mechanisms of immunosuppression in this current post. In this post, the two cell types of interest, myeloid derived suppressor cells and T regulator cells, are present in high levels with significant activity within the tumor microenvironment of cancer. They are responsible for the local immune suppression that allows for physical cancer cell escape and immune escape, resulting in metastasis [1] [2] [3] [4] [5]. Remember, metastasis is the cause of 90% of morbidity and mortality in cancer patients.

This blogpost series’s topic is the impact of low-dose, metronomic chemotherapy within the immune system in the context of cancer. So, the question of the moment should be what is the connection between metronomic chemotherapy and MDSCs? The target of action is the cancer tumor microenvironment. It seems that we keep coming back to this point of the tumor microenvironment. According to a large volume of research, there are several described mechanisms by which low-dose, metronomic chemotherapy affects MDSCs in the tumor microenvironment in cancer.

Modulation of myeloid-derived suppressor (MDSC) cells

Myeloid-derived suppressor cells (MDSC) are one of cancer’s means to the end of immunosuppression. Of course, this occurs throughout the body, but the primary flashpoint is within the tumor microenvironment. As a result of immunosuppression, it makes sense that high MDSC expression is associated with poor outcomes [6] [7].

The origin of MDSCs is the bone marrow, and they are attracted to sites of inflammation; in this case, the local tumor microenvironment is ground zero. Better than the word attracted, MDSCs are recruited to the tumor microenvironment for immunologic mischief. Within the tumor microenvironment, MDSCs suppress NK cells and cytotoxic T cells through specific inflammatory cytokine signaling and through nitric oxide production [8]. I will discuss nitric oxide synthase and nitric oxide in greater detail later.  A quote from Immunological Mechanisms of Low and Ultra-Low Dose Cancer Chemotherapy published in the journal Cancer environment in 2015 summarizes well the impact of MDSCs on the tumor microenvironment in cancer:

“…another means by which the tumor microenvironment acquires an immunosuppressive state is through the activity of a heterogenous group of cells of the myeloid lineage known as myeloid-derived suppressor cells (MDSCs).  MDSCs represent a group of both granulocytic and monocytic cells whose physiological maturation is arrested by factors in the tumor microenvironment and acquire an immunosuppressive phenotype through mediators such as iNOS, arginase 1, cyclooxygenase-2, prostaglandin E2, TGF-β, IL-10 and the induction of Treg cells” [9]

Restated in plain English, in cancer, MDSCs are recruited to the tumor microenvironment where the local signaling manipulates them within the tumor microenvironment to obtain immunosuppressive function. This recruitment and alteration of function, particularly of immune cells, is a common cancer theme and a hot topic of cancer research [10] [11]. It is important to remember that just 10-20 years ago, stating that the immune system played an essential role in carcinogenesis and metastasis would have resulted in ridicule and marginalization. Not so much now. Below are a few described mechanisms by which low-dose, metronomic chemotherapy effects MDSCs:

  1. Reduced myeloid-derived suppressor cell accumulation in the tumor microenvironment

It is important to recognize that MDSCs are released throughout the body in cancer, but specifically are recruited to lymph nodes and the tumor microenvironment. They areattracted and recruited to the inflammation present in the tumor microenvironment. But in the case of cancer, it is used for the nefarious purpose of immune suppression by cancer. Low-dose, metronomic chemotherapy inhibits this call for MDSCs to accumulate in the tumor microenvironment [12] [13] [14]. No MDSC accumulation will result in a decrease in immune suppression within the tumor microenvironment. The result is an influx of cancer-killing cytotoxic immune cells (NK cells, cytotoxic T cells, dendritic cells) into the tumor microenvironment [15]. The result is a decrease in the potential for physical cancer cell escape, immune escape, and metastasis. Now, that is an anti-cancer win, win, win. In contrast, maximum to tolerated toxicity chemotherapy appears to increase MDSC recruitment to the local tumor microenvironment [16] [17] [18].

  1. Reduced myeloid-derived suppressor cell function 11 [19] [20] [21] [22] [23]

The key point here is not just the suppression of the myeloid-derived suppressor cell number and activity, which is significant and profound enough; but the increase in the anticancer immune effects because of removing the veil of immunosuppression within the tumor microenvironment. Once the veil of immune suppression is removed, the immune system can move in for the cancer kill with NK cells, cytotoxic T cells, and dendritic cells. I think it is important to recognize that some forms of chemotherapy in the low-dose, metronomic dosing are more effective in this effect, i.e., gemzar, 5-FU, docetaxel, paclitaxel, and cisplatin, compared to cyclophosphamide. In addition to the type of chemotherapy used, the dose also impacts the effects on MDSCs [24]; thus, the importance of low-dose, metronomic chemotherapy. So, this effect is likely limited to the dose and type of chemotherapy used. Again, back to different effects with low-dose, metronomic chemotherapy versus maximum to tolerated toxicity chemotherapy.

  1. Increase in dendritic cell differentiation

Research has shown that low-dose, metronomic chemotherapy induces myeloid-derived suppressor cell differentiation into dendritic cells [25]. First, what the heck is differentiation?  Differentiation is synonymous with different or distinct. In the context of differentiation, think conversion to the distinct dendritic cell type.  Second, what are dendritic cells? Dendritic cells are classified as antigen presenting cells and are vital immune cells in the fight against cancer. Dendritic cells alert the rest of the immune system to the presence of cancer and elicit a call to action. I will discus dendritic cells and their relevance to low-dose, metronomic chemotherapy more in detail soon. More than their differentiation to dendritic cells, low-dose, metronomic chemotherapy favors differentiation to active dendritic cell types, not immune suppressing dendritic regulator types [26] [27]. This published information is more than an awakening of the mind, but really points to an awakening of the immune system to the presence of cancer within the tumor microenvironment and the rest of the body as a result of low-dose, metronomic chemotherapy.

As a result of inhibition of MDSCs via low-dose, metronomic chemotherapy, it can be expected that immunosuppression would end [28] [29], NK cell cancer-killing activity would increase [30] [31] [32] [33], and metastasis would decrease [34] [35] [36] [37]. The wins keep piling up. That is the impact of removing the MDSC veil of immunosuppression by the use of low-dose, metronomic chemotherapy.

T regulator cells

I have discussed T regulator cells in a previous post about the effects of low-dose, metronomic chemotherapy on angiogenesis in cancer. As impactful as this effect is in the process of cancer, one can argue that the more significant effect of low-dose, metronomic chemotherapy with T regulator cells is in its impact on the immune system.

A brief review on T regulator cells: T regulator cells are a type of T lymphocyte that regulates and suppresses effector (or attack) T cells and antigen-presenting cells. T regulator cells suppress both the coordination and the hand-to-hand combat effect of the immune system against foreign and domestic invaders. T regulator cells prevent misdirected immune activity in the normal world of day-to-day immune system function, such as in autoimmune disease.  From a design perspective, this check and balance make perfect sense. For example, in autoimmune disease, the immune system cannot recognize friend from foe, and T regulator immune suppression can protect the body against the immune system’s misdirected attack. In normal immune function, T regulator cell immune suppression prevents friendly fire. As so often is the case in cancer, this process of immune regulation and suppression by T regulator cells is highjacked and coopted for malicious intent. T regulator cells are immunosuppressive and prime targets for cancer’s need to support immune system suppression to promote physical escape, immune escape, and metastasis in the bizarre world of cancer.

  1. Low-dose, metronomic chemotherapy decreases the number of T regulator cells 17 [38] [39]

It is the repeated delivery of low-dose chemotherapy (metronomic) that results in the lack of T regulator cell recovery. The result is a lifting of the veil of immune suppression in the tumor microenvironment through T regulator cell suppression. Combine this with an actual increase in T effector cells, and a better anti-cancer balance of T regulator cell/T effector cell balance is achieved. Read on for a broader discussion of the T regulator/T effector ratio.

  1. Low-dose, metronomic chemotherapy decreases T regulator cell function

Low-dose, metronomic chemotherapy provides a double punch with T regulator cells. More than just a decrease in number (above), low-dose, metronomic chemotherapy decreases the function of these immune system suppressing T regulator cells [40] [41]. Number and function don’t go hand in hand. In this case, a decrease in T regulator number does equate to a decrease in T regulator cell function. The result is a decrease in the immune suppression activity, which is vital to the survival of cancer, within the tumor microenvironment.

  1. Low-dose, metronomic chemotherapy has little to no suppression effects on T effector (CD8+) cells

In addition to little or no suppression of T effector cells, research points to an increase in T effector cells by low-dose, metronomic chemotherapy [42]. This increase in T effector cells allows the immune system to shift to an anti-cancer T regulator/T effector balance. Contrast this with the effects of maximum to tolerated toxicity chemotherapy suppression of T effector cells discussed in the next point. It is not just the lower dose that yields positive immune results, but also the increased dosing frequency that targets T regulator cells’ quicker recovery time while not suppressing the T effector cells, which take much longer to recover. That was a mouth full. Essentially, the benefits of the lower dose and more frequent dosing of chemotherapy is to awaken and shift the immune system to anti-cancer action without immune suppression.

  1. Low-dose, metronomic chemotherapy increases the T regulator/T effector ratio

The importance of this point is evident in the different effects found between maximum to tolerated toxicity chemotherapy (MTTC) and low-dose, metronomic chemotherapy. Ever wonder why MTTC requires 3-4 weeks in between doses? Each treatment is like a 2 x 4 upside the head for the treatment of a headache. Oh, sure, it will take away the headache, but it will leave quite the mark and require significant recovery time. I once heard a prominent individual say that this interval was due to the chemotherapy drugs’ half-life. If only! This 3-4 week interval provides time for the body to recover from the 2 x 4 upside the head; then do it all over again. Eventually, the patient won’t get up.

The collateral damage, particularly to the immune system, is the primary reason for the 3-4 week scheduling of MTTC. It is in this time of recovery that cancer takes full advantage. At the centerpiece is T regulator cells and T effector cells. Research has shown that T regulator cells recover quicker than do T effector cells. T regulator cells can recover in 8 days, but it takes 24-199 days for T effector cells to recover [43]. This 3-4 week interval provides time for the body to recover from the 2 x 4; then do it all over again [44]. This effect is not a one-off. This increase in T regulator/T effector ratio repeatedly happens during MTTC treatment cycles, often for 6 or 12 months. The rise in T regulator cells and the disrupted T regulator/T effector ratio can last for more than three years [45]. Might this have something to do with local recurrence or metastasis? In contrast, low-dose, metronomic chemotherapy does not suppress T effector cell number or function but does suppress T regulator number and function 26 28 [46] [47]. The simple conclusion of the evidence is that maximum to tolerated toxicity chemotherapy leaves a mark, immunologically speaking, that low-dose, metronomic chemotherapy does not. And this mark may result in the mortal wound of recurrence or metastasis.

There is a very interesting connection between MDSCs and T regulator cells. Myeloid-derived suppressor cells promote T regulator cell development [48]. Essentially, the recruitment of MDSCs to the blood, lymph nodes, and tumor microenvironment creates a positive feed-forward loop of T regulator cell differentiation to double-down on immunosuppression.

In the end, the good side defeats the dark side. That is not just a Hollywood fairytale ending. The light always wins! The Death Star of cancer is the evil empire set on destruction. The force field is the dysfunctional immune system that surrounds the Death Star. The smuggled plan that targets the immune suppression force field is the research highlighted in this post. You and the immune system are the rebellion. May the force be with you.

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