Abstract
Immune checkpoint inhibitors (ICIs) have changed therapeutic algorithms in several malignancies, although intrinsic and secondary resistance is still an issue. In this context, the dysregulation of immuno-metabolism plays a leading role both in the tumor microenvironment (TME) and at the host level. In this review, we summarize the most important immune-metabolic factors and how they could be exploited therapeutically. At the cellular level, an increased concentration of extracellular adenosine as well as the depletion of tryptophan and uncontrolled activation of the PI3K/AKT pathway induces an immune-tolerant TME, reducing the response to ICIs. Moreover, aberrant angiogenesis induces a hypoxic environment by recruiting VEGF, Treg cells and immune-suppressive tumor associated macrophages (TAMs). On the other hand, factors such as gender and body mass index seem to affect the response to ICIs, while the microbiome composition (and its alterations) modulates both the response and the development of immune-related adverse events. Exploiting these complex mechanisms is the next goal in immunotherapy. The most successful strategy to date has been the combination of antiangiogenic drugs and ICIs, which prolonged the survival of patients with non-small-cell lung cancer (NSCLC) and hepatocellular carcinoma (HCC), while results from tryptophan pathway inhibition studies are inconclusive. New exciting strategies include targeting the adenosine pathway, TAMs and the microbiota with fecal microbiome transplantation.
Highlights
The use of immune checkpoint inhibitors (ICIs)—monoclonal antibodies targeting programmed death protein 1 (PD-1), programmed death protein 1 ligand (PD-L1) and CTLA-4—has yielded impressive results in many settings and is currently a cornerstone in the treatment of metastatic melanoma, non-small-cell lung carcinoma (NSCLC), renal cell carcinoma (RCC), urothelial carcinoma and Hodgkin’s lymphoma (HL) [1,2,3,4,5]
Tumor microenvironment (TME) and the physiological processes of the host play a central role in the developmetunmt oorfmreicsriosetnavnircoenmtoenICt (ITsM[E1)0a–n1d4t]h. e physiological processes of the host play a central role in the development of resistance to ICIs [10,11,12,13,14]
Results from a phase I trial, which haS enrolled 52 patients with advanced tumors, suggested that epacadostat has manageable side effects and exerts an adequate IDO1 inhibitor activity, with indirect pharmacodynamical data showing a significant reduction in plasma kynurenine levels [73]
Summary
The use of immune checkpoint inhibitors (ICIs)—monoclonal antibodies targeting programmed death protein 1 (PD-1), programmed death protein 1 ligand (PD-L1) and CTLA-4—has yielded impressive results in many settings and is currently a cornerstone in the treatment of metastatic melanoma, non-small-cell lung carcinoma (NSCLC), renal cell carcinoma (RCC), urothelial carcinoma and Hodgkin’s lymphoma (HL) [1,2,3,4,5]. 2. ResistanncuetriteontIsCthIrso:uIgmh mvasucnuleatMureetimabpaoilrimsemntDanydsdreygsrueglautlaitoionnaotf Cmeetlalbuollaicr pLaethvwealys were recently shown to affect T cell recruitment and metabolic activities in the TME [15,16,17,18]. ResistanncuetriteontIsCthIrso:uIgmh mvasucnuleatMureetimabpaoilrimsemntDanydsdreygsrueglautlaitoionnaotf Cmeetlalbuollaicr pLaethvwealys were recently shown to affect T cell recruitment and metabolic activities in the TME [15,16,17,18] These alterations, Multiipndleeemd, ecacnhpauntiismmmsunseuccehllsainstotha ehyopvo-erersepxopnrseivsessitoante,orefsuimltinmguinnTececlhl eexchkapusotionnt amndoalneecrugyle, s, loss of nutrients tihmrpoauirginhg vthaesicmumlautnuerceonimtropl aofirtmumeonrtgaronwdthdaynsdrethgeurleasptioonnseotof mICIest[a1b9–o2l1ic]. SuTphperessesoarlterations, cells (MDSC) as mediators of tumor-associated immune suppression and ICI-resistance [22,23]. A great deal of attention has recently been given to the role of macrophages and myeloid-derived suppressor cells (MDSC) as mediators of tumor-associated immune suppression and ICI-resistance [22,23]
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