Co-inhibitory receptors, such as CTLA-4 and PD-1, have an important role in regulating T cell responses and have proven to be effective targets in the setting of chronic diseases where constitutive ...co-inhibitory receptor expression on T cells dampens effector T cell responses. Unfortunately, many patients still fail to respond to therapies that target CTLA-4 and PD-1. The next wave of co-inhibitory receptor targets that are being explored in clinical trials include Lag-3, Tim-3, and TIGIT. These receptors, although they belong to the same class of receptors as PD-1 and CTLA-4, exhibit unique functions, especially at tissue sites where they regulate distinct aspects of immunity. Increased understanding of the specialized functions of these receptors will inform the rational application of therapies that target these receptors to the clinic.
The next wave of co-inhibitory receptor targets for immunotherapy has specialized roles in regulating diverse aspects of the immune response. Understanding these roles is critical for incorporating therapies against these receptors into the current immunotherapy landscape.
T cell immunoglobulin and mucin domain-containing protein 3 (TIM3), a member of the TIM family, was originally identified as a receptor expressed on interferon-γ-producing CD4
and CD8
T cells. ...Initial data indicated that TIM3 functioned as a 'co-inhibitory' or 'checkpoint' receptor, but due to the lack of a definable inhibitory signalling motif, it was also suggested that TIM3 might act as a co-stimulatory receptor. Recent studies have shown that TIM3 is part of a module that contains multiple co-inhibitory receptors (checkpoint receptors), which are co-expressed and co-regulated on dysfunctional or 'exhausted' T cells in chronic viral infections and cancer. Furthermore, co-blockade of TIM3 and programmed cell death 1 (PD1) can result in tumour regression in preclinical models and can improve anticancer T cell responses in patients with advanced cancers. Here, we highlight the developments in understanding TIM3 biology, including novel ligand identification and the discovery of loss-of-function mutations associated with human disease. In addition, we summarize emerging data from human clinical trials showing that TIM3 indeed acts as a 'checkpoint' receptor and that inhibition of TIM3 enhances the antitumour effect of PD1 blockade.
The cancer immunotherapy field has grown exponentially in the past few years, largely driven by the success of immune checkpoint blockade. Therapies targeting the immune checkpoint molecules CTLA-4 ...and PD-1 have achieved objective responses in melanoma, renal cancer, and lung cancer; however, a large number of patients are still suffering with these cancers that are not benefiting from these therapies. Moreover, several cancers have proved to be largely refractory to therapies that target CTLA-4 and PD-1. This has catalyzed interest in targeting novel immune checkpoint receptors with the goal of realizing the full potential of checkpoint blockade for treating cancer. In this regard, the immune checkpoint receptor Tim-3 exhibits several unique features that make it an intriguing candidate for the next wave of therapies that target immune checkpoints in cancer.
T cell immunoglobulin and mucin-containing molecule 3 (TIM-3), first identified as a molecule expressed on interferon-γ producing T cells
, is emerging as an important immune-checkpoint molecule, ...with therapeutic blockade of TIM-3 being investigated in multiple human malignancies. Expression of TIM-3 on CD8
T cells in the tumour microenvironment is considered a cardinal sign of T cell dysfunction; however, TIM-3 is also expressed on several other types of immune cell, confounding interpretation of results following blockade using anti-TIM-3 monoclonal antibodies. Here, using conditional knockouts of TIM-3 together with single-cell RNA sequencing, we demonstrate the singular importance of TIM-3 on dendritic cells (DCs), whereby loss of TIM-3 on DCs-but not on CD4
or CD8
T cells-promotes strong anti-tumour immunity. Loss of TIM-3 prevented DCs from expressing a regulatory program and facilitated the maintenance of CD8
effector and stem-like T cells. Conditional deletion of TIM-3 in DCs led to increased accumulation of reactive oxygen species resulting in NLRP3 inflammasome activation. Inhibition of inflammasome activation, or downstream effector cytokines interleukin-1β (IL-1β) and IL-18, completely abrogated the protective anti-tumour immunity observed with TIM-3 deletion in DCs. Together, our findings reveal an important role for TIM-3 in regulating DC function and underscore the potential of TIM-3 blockade in promoting anti-tumour immunity by regulating inflammasome activation.
Summary
While therapies targeting the co‐inhibitory or immune checkpoint receptors PD‐1 and CTLA‐4 have shown remarkable success in many cancers, not all patients benefit from these therapies. This ...has catalyzed enormous interest in the targeting of other immune checkpoint receptors. In this regard, TIGIT and CD96 have recently entered the limelight as novel immune checkpoint receptor targets. TIGIT and CD96 together with the co‐stimulatory receptor CD226 form a pathway that is analogous to the CD28/CTLA‐4 pathway, in which shared ligands and differential receptor:ligand affinities fine‐tune the immune response. Although the roles of TIGIT and CD96 as immune checkpoint receptors in T cell and natural killer cell biology are just beginning to be uncovered, accumulating data support the targeting of these receptors for improving anti‐tumor immune responses. A clear understanding of the immune cell populations regulated by TIGIT and CD96 is key to the design of immunotherapies that target these receptors in combination with other existing immune checkpoint blockade therapies.
The β-galactoside-binding protein galectin-9 is critical in regulating the immune response, but the mechanism by which it functions remains unclear. We have demonstrated that galectin-9 is highly ...expressed by induced regulatory T cells (iTreg) and was crucial for the generation and function of iTreg cells, but not natural regulatory T (nTreg) cells. Galectin-9 expression within iTreg cells was driven by the transcription factor Smad3, forming a feed-forward loop, which further promoted Foxp3 expression. Galectin-9 increased iTreg cell stability and function by directly binding to its receptor CD44, which formed a complex with transforming growth factor-β (TGF-β) receptor I (TGF-βRI), and activated Smad3. Galectin-9 signaling was further found to regulate iTreg cell induction by dominantly acting through the CNS1 region of the Foxp3 locus. Our data suggest that exogenous galectin-9, in addition to being an effector molecule for Treg cells, acts synergistically with TGF-β to enforce iTreg cell differentiation and maintenance.
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•Galectin-9 enhances Foxp3 in iTregs, but not nTregs•Galectin-9 enhances iTregs function and stability•Galectin-9-CD44-TGF-βRI results in epigenetic modification at the Foxp3 locus•Smad3 drives galectin-9 expression, which further promotes Foxp3 expression in iTregs
Galectin-9 is crucial for the generation and function of induced regulatory T (iTreg) cells, but not natural Treg cells. Kuchroo and colleagues demonstrate that exogenous galectin-9 acts synergistically with TGF-β to enforce iTreg cell differentiation and maintenance.
The intestinal mucosa constitutes an environment of closely regulated immune cells. Dendritic cells (DC) interact with the gut microbiome and antigens and are important in maintaining gut ...homeostasis. Here, we investigate DC transcriptome, phenotype and function in five anatomical locations of the gut lamina propria (LP) which constitute different antigenic environments. We show that DC from distinct gut LP compartments induce distinct T cell differentiation and cytokine secretion. We also find that PD-L1
DC in the duodenal LP and XCR1
DC in the colonic LP comprise distinct tolerogenic DC subsets that are crucial for gut homeostasis. Mice lacking PD-L1
and XCR1
DC have a proinflammatory gut milieu associated with an increase in Th1/Th17 cells and a decrease in Treg cells and have exacerbated disease in the models of 5-FU-induced mucositis and DSS-induced colitis. Our findings identify PD-L1
and XCR1
DC as region-specific physiologic regulators of intestinal homeostasis.
The immune system plays critical roles in both autoimmunity and cancer, diseases at opposite ends of the immune spectrum. Autoimmunity arises from loss of T cell tolerance against self, while in ...cancer, poor immunity against transformed self fails to control tumor growth. Blockade of pathways that preserve self-tolerance is being leveraged to unleash immunity against many tumors; however, widespread success is hindered by the autoimmune-like toxicities that arise in treated patients. Knowledge gained from the treatment of autoimmunity can be leveraged to treat these toxicities in patients. Further, the understanding of how T cell dysfunction arises in cancer can be leveraged to induce a similar state in autoreactive T cells. Here, we review what is known about the T cell response in autoimmunity and cancer and highlight ways in which we can learn from the nexus of these two diseases to improve the application, efficacy, and management of immunotherapies.
T cells are critical mediators of autoimmunity and cancer. Mangani, Yang, and Anderson review the current knowledge of the T cell response in autoimmunity and cancer and discuss how a better understanding of the nexus of these two fields can improve the application and efficacy of immunotherapies.
An improved understanding of the anti-tumor CD8+ T cell response after checkpoint blockade would enable more informed and effective therapeutic strategies. Here we examined the dynamics of the ...effector response of CD8+ tumor-infiltrating lymphocytes (TILs) after checkpoint blockade therapy. Bulk and single-cell RNA profiles of CD8+ TILs after combined Tim-3+PD-1 blockade in preclinical models revealed significant changes in the transcriptional profile of PD-1− TILs. These cells could be divided into subsets bearing characterstics of naive-, effector-, and memory-precursor-like cells. Effector- and memory-precursor-like TILs contained tumor-antigen-specific cells, exhibited proliferative and effector capacity, and expanded in response to different checkpoint blockade therapies across different tumor models. The memory-precursor-like subset shared features with CD8+ T cells associated with response to checkpoint blockade in patients and was compromised in the absence of Tcf7. Expression of Tcf7/Tcf1 was requisite for the efficacy of diverse immunotherapies, highlighting the importance of this transcriptional regulator in the development of effective CD8+ T cell responses upon immunotherapy.
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•Checkpoint blockade induces transcriptional changes in PD-1−CD8+ and PD-1+CD8+ TILs•PD-1−CD8+ TILs contain naive-, memory-precursor-, and effector-like subsets•Memory-precursor- and effector-like PD-1−CD8+ TILs expand upon checkpoint blockade•Tcf7 is required for memory-precursor-like cells and efficacy of immunotherapies
Kurtulus et al. examine the dynamics of the effector CD8+ T cell response in the tumor microenvironment in response to checkpoint blockade immunotherapy. Checkpoint blockade induced a shift from naive-like to memory-precursor- and effector-like subsets within PD-1−CD8+ T cells in tumors. The memory-precursor-like subset is maintained by the transcriptional regulator Tcf7/Tcf1, which is required for efficacy of checkpoint blockade and other immunotherapies.
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