A Report on Immunomodulation by Anticancer Drugs

Saeren Walls^*
*Correspondence: Saeren Walls, Department of Medicine, Division of Cancer Research, University of Florida, Gainesville, FL, USA, Email:

Introduction

Conventional chemotherapy works by destroying DNA or the mitotic apparatus, displaying at least some selectivity for cancer cells that proliferate rapidly. Normal tissues with a high mitotic index, such as bone marrow, hair follicles, and intestinal crypts, are also susceptible to chemotherapy's cytotoxic effects, which explain at least some of the drug's prevalent adverse effects [1]. Imatinib was rationally designed to target the oncogenic tyrosine kinase expressed by Ph+ CML cells as a result of reciprocal translocation between the long arms of chromosomes 9 and 22, resulting in a in-frame juxtaposition between BCR activator of RhoGEF and GTPase (BCR) and ABL protooncogene 1, non-receptor tyrosine kinase.

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.

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.

Conflict of Interest

The author has no conflict of interest towards the article.

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