TIM-3 as a Target for Cancer Immunotherapy and Mechanisms of Action

Du, Wenwen; Yang, Min; Turner, Abbey; Xu, Chunling; Ferris, Robert L.; Huang, Jianan; Kane, Lawrence P.; Lu, Binfeng

doi:10.3390/ijms18030645

Cited by 196 publications

(159 citation statements)

References 94 publications

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“…However, unlike PD1 +/hi Treg cells, TIM3 + intratumoral Treg cells showed enhanced suppressive capacity due to increased expression of CTLA4 and CD39 . Increased infiltration of TIM3 + CD4 + T cells or TIM3 + Treg cells is associated with poor prognosis of patients with various malignancies including non‐small cell lung cancer . Given the preclinical observations that TIM3‐blocking mAbs could reinvigorate anti‐tumor immunity, several clinical trials are actively examining the safety and efficacy of TIM3 blockade therapy in both solid tumors and lymphomas (Table ).…”

Section: Inhibitory Receptorsmentioning

confidence: 99%

Intratumoral regulatory T cells: markers, subsets and their impact on anti‐tumor immunity

et al. 2019

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Summary Regulatory T (Treg) cells play a crucial role in maintaining self‐tolerance and resolution of immune responses by employing multifaceted immunoregulatory mechanisms. However, Treg cells readily infiltrate into the tumor microenvironment (TME) and dampen anti‐tumor immune responses, thereby becoming a barrier to effective cancer immunotherapy. There has been a substantial expansion in the development of novel immunotherapies targeting various inhibitory receptors (IRs), such as CTLA4, PD1 and LAG3, but these approaches have mechanistically focused on the elicitation of anti‐tumor responses. However, enhanced inflammation in the TME could also play a detrimental role by facilitating the recruitment, stability and function of Treg cells by up‐regulating chemokines that promote Treg cell migration, and/or increasing inhibitory cytokine production. Furthermore, IR blockade may enhance Treg cell function and survival, thereby serving as a resistance mechanism against effective immunotherapy. Given that Treg cells are comprised of functionally and phenotypically heterogeneous sub‐populations that may alter their characteristics in a context‐dependent manner, it is critical to identify unique molecular pathways that are preferentially used by intratumoral Treg cells. In this review, we discuss markers that serve to identify certain Treg cell subsets, distinguished by chemokine receptors, IRs and cytokines that facilitate their migration, stability and function in the TME. We also discuss how these Treg cell subsets correlate with the clinical outcome of patients with various types of cancer and how they may serve as potential TME‐specific targets for novel cancer immunotherapies.

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Section: Inhibitory Receptorsmentioning

confidence: 99%

Intratumoral regulatory T cells: markers, subsets and their impact on anti‐tumor immunity

et al. 2019

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“…Feng et al report the percentages of Tim‐3 + cells in CD4 and CD4 + CD25 + T cell subsets were significantly lower among MS patients than controls. Notably, the differences were particularly evident in the CD4 + CD25(high) T cell subset (i.e., regulatory cells) (Du et al, ; Feng & Feng, ). Deletion of CTLA‐4 on regulatory T cells in mature animals leads to resistance to EAE., indicating that selective expression of checkpoint inhibitory molecules on effector versus regulatory cells makes it difficult to predict the therapeutic response of modulating these molecules in autoimmune disorders (Liu et al, ; Paterson et al, ).…”

Section: Comparison Of the Role Of Inflammation In Physiologic And Pamentioning

confidence: 99%

“…Such glia-directed targeting could include attempts to restore homeostatic glial function that is lost in the diseased brain. It could also potentially involve stim- cell subset (i.e., regulatory cells) (Du et al, 2017;Feng & Feng, 2016).…”

Section: Glia As Immune-therapeutic Targetsmentioning

confidence: 99%

Species differences in immune‐mediated CNS tissue injury and repair: A (neuro)inflammatory topic

Healy

Yaqubi

Ludwin

et al. 2019

Glia

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Cells of the adaptive and innate immune systems in the brain parenchyma and in the meningeal spaces contribute to physiologic functions and disease states in the central nervous system (CNS). Animal studies have demonstrated the involvement of immune constituents, along with major histocompatibility complex (MHC) molecules, in neural development and rare genetic disorders (e.g., colony stimulating factor 1 receptor [CSF1R] deficiency). Genome wide association studies suggest a comparable role of the immune system in humans. Although the CNS can be the target of primary autoimmune disorders, no current experimental model captures all of the features of the most common human disorder placed in this category, multiple sclerosis (MS). Such features include spontaneous onset, environmental contributions, and a recurrent/progressive disease course in a genetically predisposed host. Numerous therapeutic interventions related to antigen and cytokine specific therapies have demonstrated effectiveness in experimental autoimmune encephalomyelitis (EAE), the animal model used to define principles underlying immune‐mediated mechanisms in MS. Despite the similarities in the two diseases, most treatments used to ameliorate EAE have failed to translate to the human disease. As directly demonstrated in animal models and implicated by correlative studies in humans, adaptive and innate immune constituents within the systemic compartment and resident in the CNS contribute to the disease course of neurodegenerative and neurobehavioral disorders. The expanding knowledge of the molecular properties of glial cells provides increasing insights into species related variables. These variables affect glial bidirectional interactions with the immune system as well as their own production of “immune molecules” that mediate tissue injury and repair.

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“…99 Moreover, macrophages have also been observed to crosstalk to nonprofessional phagocytes, for example via the production of IGF-1, to dampen inflammatory responses on epithelial cells. 100 While presently it is not clear how individual PS receptors, or specific combinations of PS receptors and other efferocytosis receptors promote cytokine production or the polarization of professional phagocytes toward non-activating subtypes (although some PS receptors, such as TAMs and TIMs possess ITIM inhibitory motifs or have been linked to inhibitory pathways [101][102][103] ), the importance of PS receptors in immune homeostasis is clearly evident in the spectrum of inflammatory and autoimmune disorders caused by defects in PS receptors and their signaling molecules. 70 Genetic ablation of PS receptors, including members of the TAM family, members of the TIM family, SCARF1, CD300, MFG-E8, and C1q display phenotypic outcomes that manifest increased deposition of apoptotic cells in vivo, increased production of inflammatory cytokines, and often autoimmunity.…”

Section: Ps/ps-receptor Interactions and The Regulation Of Immune Hmentioning

confidence: 99%

Efferocytosis of dying cells differentially modulate immunological outcomes in tumor microenvironment

Kumar

Calianese

Birge

2017

Immunological Reviews

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Programmed cell death (apoptosis) is an integral part of tissue homeostasis in complex organisms, allowing for tissue turnover, repair, and renewal while simultaneously inhibiting the release of self antigens and danger signals from apoptotic cell-derived constituents that can result in immune activation, inflammation, and autoimmunity. Unlike cells in culture, the physiological fate of cells that die by apoptosis in vivo is their rapid recognition and engulfment by phagocytic cells (a process called efferocytosis). To this end, apoptotic cells express specific eat-me signals, such as externalized phosphatidylserine (PS), that are recognized in a specific context by receptors to initiate signaling pathways for engulfment. The importance of carefully regulated recognition and clearance pathways is evident in the spectrum of inflammatory and autoimmune disorders caused by defects in PS receptors and signaling molecules. However, in recent years, several additional cell death pathways have emerged, including immunogenic cell death, necroptosis, pyroptosis, and netosis that interweave different cell death pathways with distinct innate and adaptive responses from classical apoptosis that can shape long-term host immunity. In this review, we discuss the role of different cell death pathways in terms of their immune potential outcomes specifically resulting in specific cell corpse/phagocyte interactions (phagocytic synapses) that impinge on host immunity, with a main emphasis on tolerance and cancer immunotherapy.

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TIM-3 as a Target for Cancer Immunotherapy and Mechanisms of Action

Cited by 196 publications

References 94 publications

Intratumoral regulatory T cells: markers, subsets and their impact on anti‐tumor immunity

Intratumoral regulatory T cells: markers, subsets and their impact on anti‐tumor immunity

Species differences in immune‐mediated CNS tissue injury and repair: A (neuro)inflammatory topic

Efferocytosis of dying cells differentially modulate immunological outcomes in tumor microenvironment

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