Dying to protect: cell death and the control of T ‐cell homeostasis
Summary
T cells play a critical role in immune responses as they specifically recognize peptide/MHC complexes with their T‐cell receptors and initiate adaptive immune responses. While T cells are critical for performing appropriate effector functions and maintaining immune memory, they also can cause autoimmunity or neoplasia if misdirected or dysregulated. Thus, T cells must be tightly regulated from their development onward. Maintenance of appropriate T‐cell homeostasis is essential to promote protective immunity and limit autoimmunity and neoplasia. This review will focus on the role of cell death in maintenance of ...
Source: Immunological Reviews - April 30, 2017 Category: Allergy & Immunology Authors: Kun ‐Po Li, Sharmila Shanmuganad, Kaitlin Carroll, Jonathan D. Katz, Michael B. Jordan, David A. Hildeman Tags: INVITED REVIEW Source Type: research
Cell death and thymic tolerance
Summary
The differentiation of hematopoietic precursors into the many functionally distinct T‐cell types produced by the thymus is a complex process. It proceeds through a series of stages orchestrated by a variety of thymic microenvironments that shape the T‐cell developmental processes. Numerous cytokine and cell surface receptors direct thymocyte differentiation but the primary determinant of cell fate is the engagement of the T‐cell antigen receptor (TCR). The strength of the TCR signal and the maturation stage of the thymocyte receiving it can direct the various differentiation programs or, alternatively, end th...
Source: Immunological Reviews - April 30, 2017 Category: Allergy & Immunology Authors: Stephen R. Daley, Charis Teh, Daniel Y. Hu, Andreas Strasser, Daniel H.D. Gray Tags: INVITED REVIEW Source Type: research
Cell death and the immune system: getting to how and why
(Source: Immunological Reviews)
Source: Immunological Reviews - April 30, 2017 Category: Allergy & Immunology Authors: Douglas R. Green Tags: INTRODUCTION Source Type: research
Advances in targeting co ‐inhibitory and co‐stimulatory pathways in transplantation settings: the Yin to the Yang of cancer immunotherapy
Summary
In the past decade, the power of harnessing T‐cell co‐signaling pathways has become increasingly understood to have significant clinical importance. In cancer immunotherapy, the field has concentrated on two related modalities: First, targeting cancer antigens through highly activated chimeric antigen T cells (CAR‐Ts) and second, re‐animating endogenous quiescent T cells through checkpoint blockade. In each of these strategies, the therapeutic goal is to re‐ignite T‐cell immunity, in order to eradicate tumors. In transplantation, there is also great interest in targeting T‐cell co‐signaling, but wit...
Source: Immunological Reviews - March 3, 2017 Category: Allergy & Immunology Authors: Leslie S. Kean, Laurence A. Turka, Bruce R. Blazar Tags: INVITED REVIEW Source Type: research
Viewing Siglecs through the lens of tumor immunology
Summary
Many Siglecs function as inhibitory receptors on innate and adaptive immune cells and may contribute to the attenuation of immune responses to tumors. Siglec 9 on neutrophils and Siglec 7 on NK cells are prominent examples of inhibitory Siglecs that can potentially dampen anti‐tumor immunity. CD169 is a Siglec that may function as an adhesion molecule and a facilitator of the recognition and internalization of sialic acid decorated apoptotic bodies and exosomes derived from tumors. It can potentially contribute to both the attenuation as well as the facilitation of anti‐tumor immunity. Siglecs have been best st...
Source: Immunological Reviews - March 3, 2017 Category: Allergy & Immunology Authors: Isabella Fraschilla, Shiv Pillai Tags: INVITED REVIEW Source Type: research
TAM receptor tyrosine kinases as emerging targets of innate immune checkpoint blockade for cancer therapy
Summary
Cancer immunotherapy utilizing T‐cell checkpoint inhibitors has shown tremendous clinical success. Yet, this mode of treatment is effective in only a subset of patients. Unresponsive patients tend to have non‐T‐cell‐inflamed tumors that lack markers associated with the activation of adaptive anti‐tumor immune responses. Notably, elimination of cancer cells by T cells is critically dependent on the optimal activity of innate immune cells. Therefore, identifying new targets that regulate innate immune cell function and promote the engagement of adaptive tumoricidal responses is likely to lead to the develop...
Source: Immunological Reviews - March 3, 2017 Category: Allergy & Immunology Authors: Yemsratch T. Akalu, Carla V. Rothlin, Sourav Ghosh Tags: INVITED REVIEW Source Type: research
The CD47 ‐SIRPα signaling axis as an innate immune checkpoint in cancer
Summary
Immune checkpoint inhibitors, including those targeting CTLA‐4/B7 and the PD‐1/PD‐L1 inhibitory pathways, are now available for clinical use in cancer patients, with other interesting checkpoint inhibitors being currently in development. Most of these have the purpose to promote adaptive T cell‐mediated immunity against cancer. Here, we review another checkpoint acting to potentiate the activity of innate immune cells towards cancer. This innate immune checkpoint is composed of what has become known as the ‘don't‐eat me’ signal CD47, which is a protein broadly expressed on normal cells and often overe...
Source: Immunological Reviews - March 3, 2017 Category: Allergy & Immunology Authors: Hanke L. Matlung, Katka Szilagyi, Neil A. Barclay, Timo K. Berg Tags: INVITED REVIEW Source Type: research
The ectonucleotidases CD39 and CD73: Novel checkpoint inhibitor targets
Summary
Cancers are able to grow by subverting immune suppressive pathways, to prevent the malignant cells as being recognized as dangerous or foreign. This mechanism prevents the cancer from being eliminated by the immune system and allows disease to progress from a very early stage to a lethal state. Immunotherapies are newly developing interventions that modify the patient's immune system to fight cancer, by either directly stimulating rejection‐type processes or blocking suppressive pathways. Extracellular adenosine generated by the ectonucleotidases CD39 and CD73 is a newly recognized “immune checkpoint mediator...
Source: Immunological Reviews - March 3, 2017 Category: Allergy & Immunology Authors: Bertrand Allard, Maria Serena Longhi, Simon C. Robson, John Stagg Tags: INVITED REVIEW Source Type: research
TIGIT and CD96: new checkpoint receptor targets for cancer immunotherapy
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...
Source: Immunological Reviews - March 3, 2017 Category: Allergy & Immunology Authors: William C. Dougall, Sema Kurtulus, Mark J. Smyth, Ana C. Anderson Tags: INVITED REVIEW Source Type: research
Tim ‐3 and its role in regulating anti‐tumor immunity
Summary
Immunotherapy is being increasingly recognized as a key therapeutic modality to treat cancer and represents one of the most exciting treatments for the disease. Fighting cancer with immunotherapy has revolutionized treatment for some patients and therapies targeting the immune checkpoint molecules such as CTLA‐4 and PD‐1 have achieved durable responses in melanoma, renal cancer, Hodgkin's diseases and lung cancer. However, the success rate of these treatments has been low and a large number of cancers, including colorectal cancer remain largely refractory to CTLA‐4 and PD‐1 blockade. This has provided impet...
Source: Immunological Reviews - March 3, 2017 Category: Allergy & Immunology Authors: Madhumita Das, Chen Zhu, Vijay K. Kuchroo Tags: INVITED REVIEW Source Type: research
LAG3 (CD223) as a cancer immunotherapy target
Summary
Despite the impressive impact of CTLA4 and PD1‐PDL1‐targeted cancer immunotherapy, a large proportion of patients with many tumor types fail to respond. Consequently, the focus has shifted to targeting alternative inhibitory receptors (IRs) and suppressive mechanisms within the tumor microenvironment. Lymphocyte activation gene‐3 (LAG3) (CD223) is the third IR to be targeted in the clinic, consequently garnering considerable interest and scrutiny. LAG3 upregulation is required to control overt activation and prevent the onset of autoimmunity. However, persistent antigen exposure in the tumor microenvironment ...
Source: Immunological Reviews - March 3, 2017 Category: Allergy & Immunology Authors: Lawrence P. Andrews, Ariel E. Marciscano, Charles G. Drake, Dario A. A. Vignali Tags: INVITED REVIEW Source Type: research
Immunoregulatory functions of VISTA
Summary
Utilization of negative checkpoint regulators (NCRs) for cancer immunotherapy has garnered significant interest with the completion of clinical trials demonstrating efficacy. While the results of monotherapy treatments are compelling, there is increasing emphasis on combination treatments in an effort to increase response rates to treatment. One of the most recently discovered NCRs is VISTA (V‐domain Ig‐containing Suppressor of T cell Activation). In this review, we describe the functions of this molecule in the context of cancer immunotherapy. We also discuss factors that may influence the use of anti‐VISTA ...
Source: Immunological Reviews - March 3, 2017 Category: Allergy & Immunology Authors: Elizabeth C. Nowak, J. Louise Lines, Frederick S. Varn, Jie Deng, Aurelien Sarde, Rodwell Mabaera, Anna Kuta, Isabelle Le Mercier, Chao Cheng, Randolph J. Noelle Tags: INVITED REVIEW Source Type: research
New checkpoints in cancer immunotherapy
Summary
Immune responses must be fine‐tuned to allow effective clearance of invading pathogens, while maintain tolerance to self‐antigens. T cells are the major effector cells for fighting and killing tumor cells. Immune checkpoints play a pivotal role in T cell activation, and determine the functional outcome of T cell receptor (TCR) signaling. The blockade of immune checkpoints CTLA‐4 and PD‐1 has already been one of the most successful cancer immunotherapies. In this review, we will focus on three novel inhibitory B7 family checkpoint molecules, B7‐H3, B7S1 and VISTA. The aim of this article is to summarize th...
Source: Immunological Reviews - March 3, 2017 Category: Allergy & Immunology Authors: Ling Ni, Chen Dong Tags: INVITED REVIEW Source Type: research
Potential targeting of B7 ‐H4 for the treatment of cancer
Summary
Observations noting the presence of white blood cell infiltrates within tumors date back more than a century, however the cellular and molecular mechanisms regulating tumor immunity continue to be elucidated. The recent successful use of monoclonal antibodies to block immune regulatory pathways to enhance tumor‐specific immune responses for the treatment of cancer has encouraged the identification of additional immune regulatory receptor/ligand pathways. Over the past several years, a growing body of data has identified B7‐H4 (VTCN1/B7x/B7S1) as a potential therapeutic target for the treatment of cancer. The po...
Source: Immunological Reviews - March 3, 2017 Category: Allergy & Immunology Authors: Joseph R. Podojil, Stephen D. Miller Tags: INVITED REVIEW Source Type: research
The third group of the B7 ‐CD28 immune checkpoint family: HHLA2, TMIGD2, B7x, and B7‐H3
Summary
The B7‐CD28 family of ligands and receptors play important roles in T‐cell co‐stimulation and co‐inhibition. Phylogenetically they can be divided into three groups. The recent discovery of the new molecules (B7‐H3 [CD276], B7x [B7‐H4/B7S1], and HHLA2 [B7H7/B7‐H5]/TMIGD2 [IGPR‐1/CD28H]) of the group III has expanded therapeutic possibilities for the treatment of human diseases. In this review, we describe the discovery, structure, and function of B7‐H3, B7x, HHLA2, and TMIGD2 in immune regulation. We also discuss their roles in important pathological states such as cancers, autoimmune diseases, tra...
Source: Immunological Reviews - March 3, 2017 Category: Allergy & Immunology Authors: Murali Janakiram, Urvi A. Shah, Weifeng Liu, Aimin Zhao, Mark P. Schoenberg, Xingxing Zang Tags: INVITED REVIEW Source Type: research
