The Role of Sphingolipids in Cancer Immunotherapy

Abstract

Immunotherapy is now considered an innovative and strong strategy to beat metastatic, drug-resistant, or relapsing tumours. It is based on the manipulation of several mechanisms involved in the complex interplay between cancer cells and immune system that culminates in a form of immune-tolerance of tumour cells, favouring their expansion. Current immunotherapies are devoted enforcing the immune response against cancer cells and are represented by approaches employing vaccines, monoclonal antibodies, interleukins, checkpoint inhibitors, and chimeric antigen receptor (CAR)-T cells. Despite the undoubted potency of these treatments in some malignancies, many issues are being investigated to amplify the potential of application and to avoid side effects. In this review, we discuss how sphingolipids are involved in interactions between cancer cells and the immune system and how knowledge in this topic could be employed to enhance the efficacy of different immunotherapy approaches. In particular, we explore the following aspects: how sphingolipids are pivotal components of plasma membranes and could modulate the functionality of surface receptors expressed also by immune cells and thus their functionality; how sphingolipids are related to the release of bioactive mediators, sphingosine 1-phosphate, and ceramide that could significantly affect lymphocyte egress and migration toward the tumour milieu, in addition regulating key pathways needed to activate immune cells; given the renowned capability of altering sphingolipid expression and metabolism shown by cancer cells, how it is possible to employ sphingolipids as antigen targets.

The key role of sphingolipid metabolism in cancer: New therapeutic targets, diagnostic and prognostic values, and anti-tumor immunotherapy resistance

“…Ceramides modified with nanomaterials can further modulate the efficacy of tumor immunotherapy. Nanoliposomal C6-ceramide (LipC6) not only induces apoptosis and prevents HCC-induced immune tolerance in HCC cells, it also significantly decelerates the growth of liver cancer cells, enhances tumor-infiltrating CD8 + T cells, and inhibits tumor-resident CD4 + CD25 + forkhead box protein P3 (FoxP3 + ) Treg cells in combination with anti-CTLA4 Ab ( 102 ). Molecular studies have shown that combination therapy inhibits the transcription factors Krüppel-like factor 2, FoxP3 and CTLA4 ( 102 ).…”

“…Nanoliposomal C6-ceramide (LipC6) not only induces apoptosis and prevents HCC-induced immune tolerance in HCC cells, it also significantly decelerates the growth of liver cancer cells, enhances tumor-infiltrating CD8 + T cells, and inhibits tumor-resident CD4 + CD25 + forkhead box protein P3 (FoxP3 + ) Treg cells in combination with anti-CTLA4 Ab ( 102 ). Molecular studies have shown that combination therapy inhibits the transcription factors Krüppel-like factor 2, FoxP3 and CTLA4 ( 102 ). The dysregulation of sphingolipid metabolism is also frequently associated with cancer stem cells ( 103 , 104 ) and consequently generates a series of tumor immune-related effects; this situation suggests that ceramide is a key player in cancer immunotherapy ( 104 ).…”

Signaling controversy and future therapeutical perspectives of targeting sphingolipid network in cancer immune editing and resistance to tumor necrosis factor-α immunotherapy

“…Several intrinsic factors and molecular mechanisms have been found responsible for the development of TNF-resistance, including mutation and downregulation of DR expression [ 10 ], activation of anti-apoptotic effectors (such as superoxide dismutase (MnSOD or SOD) [ 16 , 17 ] and mitogen-activated protein kinase (MAPK)) [ 18 ]), diversion of nuclear transcription factor signaling (including nuclear factor kappa-light-chain-enhancer of activated B cells κB (NF-κB)) signaling [ 19 ]), and other pro-survival mechanisms. One of the survival pathways associated with anti-apoptotic and growth-promoting mechanisms is represented by the sphingolipid signaling axis [ 20 , 21 ]. Sphingolipids are involved in the regulation of numerous intracellular mechanisms, both as mediators and effectors of signaling.…”

The Role of Sphingolipid Signaling in Oxidative Lung Injury and Pathogenesis of Bronchopulmonary Dysplasia

“…Lately, its role as regulatory molecules in various functions such as immune response, cell proliferation, differentiation, apoptosis, and angiogenesis were identified [34]. Dysregulation in sphingolipid signaling pathway is noted in both pulmonary and nonpulmonary diseases [35][36][37][38][39][40]. Interestingly, alteration in sphingolipid signaling axis, as manifested by increased levels of ceramides S1P and S1P synthesizing enzyme, sphingosine kinase 1 (SPHK1), was observed in lung and tracheal aspirates of BPD patients [29,30,41].…”