Not All Immune Checkpoints Are Created Equal

Abstract

Antibodies that block T cell inhibition via the immune checkpoints CTLA-4 and PD-1 have revolutionized cancer therapy during the last 15 years. T cells express additional inhibitory surface receptors that are considered to have potential as targets in cancer immunotherapy. Antibodies against LAG-3 and TIM-3 are currently clinically tested to evaluate their effectiveness in patients suffering from advanced solid tumors or hematologic malignancies. In addition, blockade of the inhibitory BTLA receptors on human T cells may have potential to unleash T cells to effectively combat cancer cells. Much research on these immune checkpoints has focused on mouse models. The analysis of animals that lack individual inhibitory receptors has shed some light on the role of these molecules in regulating T cells, but also immune responses in general. There are current intensive efforts to gauge the efficacy of antibodies targeting these molecules called immune checkpoint inhibitors alone or in different combinations in preclinical models of cancer. Differences between mouse and human immunology warrant studies on human immune cells to appreciate the potential of individual pathways in enhancing T cell responses. Results from clinical studies are not only highlighting the great benefit of immune checkpoint inhibitors for treating cancer but also yield precious information on their role in regulating T cells and other cells of the immune system. However, despite the clinical relevance of CTLA-4 and PD-1 and the high potential of the emerging immune checkpoints, there are still substantial gaps in our understanding of the biology of these molecules, which might prevent the full realization of their therapeutic potential. This review addresses PD-1, CTLA-4, BTLA, LAG-3, and TIM-3, which are considered major inhibitory immune checkpoints expressed on T cells. It provides summaries of our current conception of the role of these molecules in regulating T cell responses, and discussions about major ambiguities and gaps in our knowledge. We emphasize that each of these molecules harbors unique properties that set it apart from the others. Their distinct functional profiles should be taken into account in therapeutic strategies that aim to exploit these pathways to enhance immune responses to combat cancer.

Memory CD4+ T Cells in Immunity and Autoimmune Diseases

“…Immune checkpoints/ T cell exhaustion PD-1 [196] BTLA [197] LAG-3 [198] TIM-3 promotes effector responses [199] CTLA-4 [200] LAG-3 [198] TIM-3 suppresses memory differentiation [199] [ [196][197][198][199][200] Antigen persistence…”

Expressions of inhibitory checkpoint molecules in acute and chronic HBV and HCV infections: Implications for therapeutic monitoring and personalized therapy

“…However, its expression has also been demonstrated on innate immune cells, including monocytes and dendritic cells (DCs). 54 The herpes virus entry mediator (HVEM) is the only identified ligand for BTLA. 54 Studies on the role of BTLA during acute hepatitis are also limited.…”

“…54 The herpes virus entry mediator (HVEM) is the only identified ligand for BTLA. 54 Studies on the role of BTLA during acute hepatitis are also limited. In HCV infection, TIGIT + PD-1 + BTLA + TIM-3 − HCV-specific CD4 + T cells were the predominant phenotypes found in acute HCV patients.…”

LAG-3 and PD-1+LAG-3 inhibition promote anti-tumor immune responses in human autologous melanoma/T cell co-cultures

“…9 This natural principle of modulating T cell function with inhibitory receptors is exploited by tumors, which favor the expression of these receptors/ligands through various processes that are only partially understood, in order to preclude T cell function. [10][11][12] Dysfunctional (coined "exhausted") T cells in tumors display a transcriptional program that reflects chronic antigen stimulation and the effects of additional intra-tumoral factors such as hypoxia and particular immune cells, cytokines, and metabolites. 4 Based on numerous independent studies illustrating the powerful role of the receptor CTLA-4 (Cytotoxic T Lymphocyte Antigen 4) in the inhibition of T cell responses, 13 a number of clinical trials were launched to determine whether anti-CTLA-4 blocking monoclonal antibodies (mAb) could enhance the activity of tumor-specific T cells and provide clinical benefit to melanoma patients.…”

“…Among potential targets, LAG-3 (Lymphocyte Activated Gene 3), BTLA (B and T Lymphocyte Attenuator) and TIM-3 (T cell Immunoglobulin and Mucin-containing protein 3) have emerged as possible candidates based on encouraging results in pre-clinical studies in mouse models and in clinical trials. 12,20,21 In the model of CT26 colon adenocarcinoma, the combination of anti-PD-L1 and anti-TIM-3 increased tumor control and cytokine production by T cells. 22 Similarly, the combination of anti-PD-1 and anti-LAG -3 antibodies restrained tumor development in mice injected with Sa1N fibrosarcoma or MC38 colon adenocarcinoma.…”