Anticancer Drugs' Immunomodulating Effects: An Overview

Samiel Rog^*
*Correspondence: Samiel Rog, Neonatal Intensive Care Unit, University Hospitals Leuven, Leuven, Belgium, Email:

Introduction

Conventional chemotherapy targets cancer cells that multiply quickly by destroying DNA or the mitotic apparatus, at least in part. Chemotherapy's cytotoxic effects can also harm healthy tissues with a high mitotic index, like bone marrow, hair follicles, and intestinal crypts, which helps to explain at least some of the drug's common side effects [1]. As a result of reciprocal translocation between chromosomes 9 and 22, which produced an in-frame juxtaposition between BCR activator of RhoGEF and GTPase (BCR) and ABL proto-oncogene 1, non-receptor tyrosine kinase, imatinib was purposefully created to target the oncogenic tyrosine kinase expressed by Ph+ CML cells.

Description

Immunomodulation

Imatinib and practically all other targeted anticancer drugs have immunostimulatory or immunosuppressive effects that can (positively or adversely) influence treatment success, according to a significant body of preclinical and clinical data. CDKs are a family of serine/threonine kinases that control cell cycle progression as well as other cellular functions such as DNA repair, transcription, and metabolism. Deregulated CDK activity has emerged as a driver of uncontrolled proliferation in a range of human neoplasms [2], resulting in the approval of three separate CDK4/CDK6 inhibitors for treatment in patients with hormone receptor (HR)+ breast cancer recently. Gain-offunction mutations in the proto-oncogenes KRAS, PI3KCA, or B-Raf, as well as phosphatase and tensin homolog (PTEN) deletions, result in constitutive mitogenic signalling via AKT serine/threonine kinase 1 (AKT1) and mechanistic target of rapamycin (MTOR) or MEK, resulting in several human tumours.

Anticancer drugs

Multiple mechanisms facilitate the formation of an immunosuppressive microenvironment in malignant cells with activated KRAS and BRAF mutations [3,4]. As a result, BRAF and MEK inhibitors (including the FDA-approved agents vemurafenib, dabrafenib, and trametinib) mediate a variety of cancer-cell-dependent immunostimulatory effects, including (1) upregulation of TAAs (2) improved antigen presentation on MHC class I molecules (3) induction of ICD (4) secretion of TH1 cytokines like CXCL9 and CXCL10). Loss of antigen presentation, TEFF cell exhaustion, and tumour infiltration by immunosuppressive cells have all been reported when malignancies advance on KRAS, BRAF, or MEK inhibitors in both preclinical and clinical settings, indicating the therapeutic importance of these results [5,6].

This is due, at least in part; to MEK signaling's function in the priming of naive T cells as well as the protection of tumor-infiltrating CD8+ CTLs from the fatal effects of persistent TCR stimulation. Phosphatidylinositol-4,5- bisphosphate 3-kinase catalytic subunit delta (Pik3cd) deletion, on the other hand, appears to make TEFF cells less vulnerable to the immunostimulatory effects of ICIs, suggesting that TREG cell depletion may be the key therapeutic component of systemic PI3Kd inhibition. T cells treated ex vivo with PI3Kd, AKT, and MTOR inhibitors, on the other hand, tend to retain a poorly differentiated memory phenotype with increased proliferative capacities, resulting in higher persistence and superior effector functions when adopted into tumorbearing animals.

In an effort to create effective anti-cancer therapies, anti-proliferative and cytotoxic agents are frequently used individually, in combination with one another, and/or with different types of treatment modalities. In the majority of cases, drug regimens use the agents at or close to the maximum tolerated dose (MTD) with the goal of eliminating the most neoplastic cells possible. However, it is now becoming more and more obvious that a number of these drugs also have antitumor effects on the host, as well as effects on immune responses and angiogenesis. Some of these effects may also have therapeutic value. It should be noted that although the MTD typically yields the maximum direct antitumor effects, additional potentially advantageous actions on host biological systems may occur.

In an effort to create effective anti-cancer therapies, anti-proliferative and cytotoxic agents are frequently used individually, in combination with one another, and/or with different types of treatment modalities. In the majority of cases, drug regimens use the agents at or close to the maximum tolerated dose (MTD) with the goal of eliminating the most neoplastic cells possible. However, it is currently becoming more and more obvious that a number of these agents also have an impact on host processes like angiogenesis and immune responses in addition to their antitumor effects, some of which may have therapeutic value. It should be noted that while the MTD typically results in the greatest direct antitumor effects, optimal induction results in the greatest additional potentially beneficial effects on host biological systems.

In experimental systems, the anti-angiogenic properties of anti-cancer medications like adriamycin and cyclophosphamide are being investigated. Whether administered alone or in conjunction with anti-angiogenic agents, these medications are effective when administered in doses and ways that differ from those typically used in cancer chemotherapy. For the past 40 years, anti-cancer drug effects on immune systems have been studied, but only in the last ten or so years have the mechanisms underlying these effects started to be understood.

Based on their anti-proliferative and cytotoxic effects, which also determine their antitumor effects, anti-cancer medications were initially believed to be immunosuppressive. However, it became clear that some of these agents can have curative effects in tumour models used in research as early as the 1960s because the host defences against the tumour work in concert with these agents. Therefore, it was determined that these agents can at least act in a way that allows the host's antitumor defences to be activated, much like they do during anti-infection therapies. This initial, oversimplified hypothesis had to be modified as more information became available to take into account the idea that, at least in some cases, these agents can either directly or indirectly stimulate immune responses [7].

Thus, it was discovered that cyclophosphamide and other alkylating agents, 6-mercaptopurine, methotrexate, 5-fluorouracil, arabinosylcytosine, vinblastine, vincristine, doxorubicin, bleomycin, mitomycin C, cis-platinum, and nitrosourea all induced an augmentation of the immune response at low to moderate doses. It has only recently been discovered that taxol stimulates immune system macrophage activity. Doxorubicin is used as an illustration to show how complicated the immunomodulation brought on by some.

The antitumor effects of cytotoxic macrophages (MO) and cytotoxic T lymphocytes (CTL) were also enhanced when mice were treated with doxorubicin at moderate doses, which has therapeutic antitumor effects in mouse tumour model systems. Increased accessory function, IL-1, prostaglandin E2, and tumour necrosis factor (TNF) production were also associated with the drug's stimulation of MO activation. Natural killer (NK) cells were inhibited in the spleen but stimulated in the peritoneal cavity, and the inhibitory effects were reversed by indomethacin. Additionally, depending on the circumstances, the activity of lymphokine activated killer (LAK) cells may be increased or decreased.

Conclusion

Imatinib, which was developed to reduce constitutive signalling from the BCR-ABL1 chimaera by targeting the kinase domain of ABL1, turns out to inhibit a number of clinically relevant kinases. No targeted anticancer agent was purposefully designed to mediate immunomodulatory effects when immunomodulation actually stems from the inhibition of the intended molecular target in malignant cells, implying that various proteins that support oncogenesis also influence the ability of neoplastic cells to deliver immunostimulatory or immunosuppressive signals.

Acknowledgement

None.

Conflict of Interest

There are no conflicts of interest by author.

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