Platinum Derivatives Effects on Anticancer Immune Response

Abstract

Along with surgery and radiotherapy, chemotherapeutic agents belong to the therapeutic arsenal in cancer treatment. In addition to their direct cytotoxic effects, these agents also impact the host immune system, which might enhance or counteract their antitumor activity. The platinum derivative compounds family, mainly composed of carboplatin, cisplatin and oxaliplatin, belongs to the chemotherapeutical arsenal used in numerous cancer types. Here, we will focus on the effects of these molecules on antitumor immune response. These compounds can induce or not immunogenic cell death (ICD), and some strategies have been found to induce or further enhance it. They also regulate immune cells' fate. Platinum derivatives can lead to their activation. Additionally, they can also dampen immune cells by selective killing or inhibiting their activity, particularly by modulating immune checkpoints' expression.Cell death is characterized by morphological alterations that have been historically used by The Nomenclature Committee on Cell Death (NCCD) to classify this cellular process into three different forms: type I or apoptosis, type II or autophagy, and type III or necrosis. Although limited, this morphological classification remains widely used, independently of essential molecular aspects of the cell death process. New NCCD classifications focus on molecular mechanisms and on the biochemistry of intracellular signalization effectors. Currently, it is clear that connections and overlaps exist between the different types of cell death. The majority of chemotherapeutic drugs are known to induce apoptosis or necrosis. Engagement of a particular type of cell death depends on the stress type, interaction between induction factors, genetic cell background, organelle content and enzymatic proteins arsenal [3,4].The action of chemotherapy relies not only on its cytotoxic effect on cancer cells, but also on its ability to affect immune cells.

Efficacy and Safety of Checkpoint Inhibitor Treatment in Patients with Advanced Renal or Urothelial Cell Carcinoma and Concomitant Chronic Kidney Disease: A Retrospective Cohort Study

“…However, in our cohort, a high proportion of UC CKD patients, 54.4%, still received cisplatin-based chemotherapy. Preclinical data support a synergism between cisplatin and PD-L1 blockade through enhanced T cell responses and PD-L1 expression on tumor cells [ 34 , 35 ]. Larger cohorts of patients with CKD and CPI treatment are needed to confirm this result.…”

Calreticulin—Multifunctional Chaperone in Immunogenic Cell Death: Potential Significance as a Prognostic Biomarker in Ovarian Cancer Patients

“…In contrast, oxaliplatin, a third-generation platinum analogue, seems to be indisputable type I ICD inducer. On the other hand, physical methods, such as photodynamic therapy, high hydrostatic pressure or molecules as oncolytic viruses are the example of type II inducers [ 30 , 35 , 36 , 37 ]. Both types of inducers, by the combined action of ER stress and ROS generation which activates danger signaling pathways, are able to trigger the timely release or membrane exposure of a series of DAMPs.…”

“…They are alkylating agents, which principal action is based on the formation of intra- and inter-strand connection between DNA strands. However, platinum compounds exert also other effects i.e., they can increase intracellular amount of ROS influencing ER stress [ 37 , 117 , 118 ]. Despite the high controversy, many reports clearly indicate that cisplatin or its analogs can effectively induce the expression of ecto-CRT on ovarian cancer cells.…”

Targeting the immune milieu in gastrointestinal cancers

“…Depletes MDSCs [150] Increases IFNy, IL1b and IL-17 production [150,151] Activation of NLRP3 inflammasome [152] Platinum agents Increased IFNy, TNFa production through upregulation of CD8 T cells [153] Upregulation of HMGB-1 [154,155] Upregulation of MHC1 expression [156] Anthracyclines Upregulation of HMGB-1 expression [157] Increased expression of type 1 interferons [158] Upregulation of IFNy and STING pathway [159] Taxanes Increased production of IFNb [160] Formation of micronuclei DNA and activation of STING pathway [161] Increased expression of MHC class I expression [160] Gemcitabine Depletes circulating Tregs [162] Depletion of MDSCs [163] CD cluster of differentiation, DNA deoxyribonucleic acid, HMGB-1 high mobility group box 1, IFN interferon, IL interleukin, MDSC myeloid-derived suppressor cells, MHC major histocompatibility complex, NLRP3 NACHT LRR and PYD domains-containing protein 3, NK natural killer, STING stimulator of interferon genes, TNF-a tumour necrosis factor alpha, Tregs T regulatory cells is also data to support the use of ramucirumab, a monoclonal antibody to VEGFR-2, in combination with paclitaxel in advanced OGA in the later line setting [79]. Sorafenib and lenvatinib, both with anti-VEGF activity, are also effective for treatment of advanced HCC [80].…”