A comprehensive review on the role of co-signaling receptors and Treg homeostasis in autoimmunity and tumor immunity

Abstract

The immune system ensures optimum T-effector (Teff) immune responses against invading microbes and tumor antigens while preventing inappropriate autoimmune responses against self-antigens with the help of T-regulatory (Treg) cells. Thus, Treg and Teff cells help maintain immune homeostasis through mutual regulation. While Tregs can contribute to tumor immune evasion by suppressing anti-tumor Teff response, loss of Treg function can result in Teff responses against self-antigens leading to autoimmune disease. Thus, loss of homeostatic balance between Teff/Treg cells is often associated with both cancer and autoimmunity. Co-stimulatory and co-inhibitory receptors, collectively known as co-signaling receptors, play an indispensable role in the regulation of Teff and Treg cell expansion and function and thus play critical roles in modulating autoimmune and anti-tumor immune responses. Over the past three decades, considerable efforts have been made to understand the biology of co-signaling receptors and their role in immune homeostasis. Mutations in co-inhibitory receptors such as CTLA4 and PD1 are associated with Treg dysfunction, and autoimmune diseases in mice and humans. On the other hand, growing tumors evade immune surveillance by exploiting co-inhibitory signaling through expression of CTLA4, PD1 and PDL-1. Immune checkpoint blockade (ICB) using anti-CTLA4 and anti-PD1 has drawn considerable attention towards co-signaling receptors in tumor immunology and created renewed interest in studying other co-signaling receptors, which until recently have not been as well studied. In addition to co-inhibitory receptors, co-stimulatory receptors like OX40, GITR and 4-1BB have also been widely implicated in immune homeostasis and T-cell stimulation, and use of agonistic antibodies against OX40, GITR and 4-1BB has been effective in causing tumor regression. Although ICB has seen unprecedented success in cancer treatment, autoimmune adverse events arising from ICB due to loss of Treg homeostasis poses a major obstacle. Herein, we comprehensively review the role of various co-stimulatory and co-inhibitory receptors in Treg biology and immune homeostasis, autoimmunity, and anti-tumor immunity. Furthermore, we discuss the autoimmune adverse events arising upon targeting these co-signaling receptors to augment anti-tumor immune responses.

The Role of GITR/GITRL Interaction in Autoimmune Diseases

“…In effector CD4 + T cells, the predominated conclusion is triggering GITR on CD4 + CD25 - T cells can induce the survival, activation and proliferation of CD4 + T cells, and the effect is mainly dependent on TCR stimulation and CD28 co-triggering ( 13 ). However, several researches reported that GITR/GITRL interaction could also contribute to immune homeostasis by regulating effector CD4 + T cells ( 14 , 15 ). GITR engagement can mediate cell apoptosis.…”

Functional effects of chimeric antigen receptor co-receptor signaling domains in human Tregs

“…Within the TNFR family, we selected: 4-1BB as this co-receptor is beneficial for the longevity of CAR-T cells (Long et al, 2015;Song et al, 2011) and in models of autoimmunity is beneficial for Tregs (Kumar et al, 2018); OX40 and GITR, which promote Tregs in certain contexts (Kumar et al, 2018); and TNFR2 which stimulates Treg proliferation and suppression Pierini et al, 2016).…”

“…Due to the extensive evidence for the important role of CD28 co-stimulation in Tregs (Esensten et al, 2016), the majority of CAR-Treg studies selected this protein as the source of co-stimulation. However, as with conventional T cells (Tconvs), Tregs express a number of coreceptors that provide co-stimulatory or co-inhibitory signals (reviewed in (Kumar et al, 2018)), the functional relevance of which may differ from that in Tconvs, and vary depending on the tissue/disease context. An additional consideration is that the vast majority of studies which have defined co-receptor function in Tregs used genetic-deletion models in which co-receptors of interest were absent throughout Treg development, thus making it difficult to infer function in the fully differentiated cells which would be used for CAR engineering.…”

From chemotherapy to biological therapy: A review of novel concepts to reduce the side effects of systemic cancer treatment (Review)

“…Early recognition and quick intervention, for instance with corticosteroids, is essential. A previous comprehensive review focused on the role of cosignaling (costimulatory or co-inhibitory) receptors and Treg homeostasis in autoimmunity and tumor immunity ( 64 ).…”