ChemoImmunoModulation: Immune Regulation by the Antineoplastic Chemotherapeutic Agents

Abstract

Since 1948, when Farber et al. introduced aminopterin, the first chemotherapeutic agent, more than 100 such agents have come into use. Initially, antitumor chemotherapies were thought to produce only antiproliferative or cytotoxic effects on dividing tumor cells as it was often associated with the damage to healthy tissues and the development of resistant tumor clones. However, that view has been changing as a consequence of recent demonstrations that several antineoplastic drugs, even at low doses, have antiangiogenic and sometimes immunomodulating effects. In addition, new studies indicate that lowering the dose of conventional cytotoxic agents and combining chemotherapy with other modalities may not only decrease the toxicity of conventional chemotherapy, but also up-regulate the efficacy of different anticancer therapies. Giving chemotherapy in this manner has several potential advantages, including impediment of the onset of mutation-dependent mechanisms of acquired drug resistance and increase in the efficacy and durability of combinatorial therapeutic modalities. Certain "immunogenic" forms of cancer chemotherapy may cause indirect activation of immune cells due to the accessibility of tumor antigens and certain "danger" signals. Furthermore, new findings indicate that several chemotherapeutic agents can directly activate immune cells when used in ultra low noncytotoxic concentrations, the new phenomenon that was termed chemoimmunomodulation. The goal of this review is to analyze the immune modulating properties of antineoplastic chemotherapeutic agents and present new evidence of the immunostimulating potentials of several agents used in low and ultra low nontoxic doses. Therapeutic potentials of combined chemo-immunotherapeutic regimens have been extensively reviewed in a variety of recent publications and will not be discussed.

Tumor Microenvironment and Myeloid-Derived Suppressor Cells

“…In our recent studies, we have shown that the administration of chemotherapeutic drug paclitaxel at ultra-low noncytotoxic doses, previously described as chemoimmunomodulation [106], in healthy C57BL/6 mice significantly reduced the amount of CD11b + Gr1 + immature myeloid cells [107] that are known as an MDSC counterpart in normal mice [28]. Such MDSC down-regulation was associated with increased natural killer cell frequencies in the bone marrow and their ability to produce IFN-γ.…”

Immunological Mechanisms of Low and Ultra-Low Dose Cancer Chemotherapy

“…However, recent research efforts present compelling evidence that suggests that these same drugs given in low or ultra-low doses may also hold clinical utility through their ability to promote antitumor immunity [2]. If successful, employing these drugs in such a manner would allow for prevention of the significant morbidity associated with current chemotherapy regimens as well as potentially abrogate the potential for the development of tumor resistance.…”

“…More recently, there has been increasing interest in the application of traditional chemotherapeutic agents for the purpose of manipulating the immune system to produce favorable antitumor immune responses using low-dose chemotherapy ("immunogenic" chemotherapy) [11] or even ultralow doses of chemotherapeutic agents, a term coined "chemoimmunomodulation" [2]. It is clear that there is significant interaction between chemotherapeutic drugs, dying tumor cells, and local immune cells that have various effects on tumor immunogenicity, and many of these effects have been previously described using traditional, MTD drug regimen strategies [12].…”

“…Since the advent of the age of systemic cancer drug therapy, treatment strategies have been dominated by the use of cytotoxic chemotherapeutic agents for the majority of cancer types. From 1948, when Farber et al introduced aminopterin, the first chemotherapeutic agent, more than 100 such agents have come into use in clinical practice [2]. While significant advances have been made since that time, such as the development of novel classes of drugs and the use of combinatorial therapies, most drug regimens continue to be based on the traditional, maximum tolerated dose (MTD) regimen.…”

Immunomodulatory effects of low dose chemotherapy and perspectives of its combination with immunotherapy

“…In fact, the myelosuppressive effect of several drugs is well described. [6][7][8][9][10] As recently reviewed by Shurin et al 10 the main immunosuppressive effect of high dose chemotherapy is the depletion of T lymphocytes. Both CD4þ and CD8þ are affected by cytotoxic drugs but the normal levels of peripheral CD4þ cells are more slowly restored than CD8þ.…”