Oncology Meets Immunology: The Cancer-Immunity Cycle

The immune system has evolved to mount an effective defense against pathogens and to minimize deleterious immune-mediated inflammation caused by commensal microorganisms, immune responses against self and environmental antigens, and metabolic inflammatory disorders. Regulatory T (Treg) cell–mediated suppression serves as a vital mechanism of negative regulation of immune-mediated inflammation and features prominently in autoimmune and autoinflammatory disorders, allergy, acute and chronic infections, cancer, and metabolic inflammation. The discovery that Foxp3 is the transcription factor that specifies the Treg cell lineage facilitated recent progress in understanding the biology of regulatory T cells. In this review, we discuss cellular and molecular mechanisms in the differentiation and function of these cells.

Regulatory T Cells: Mechanisms of Differentiation and Function

This year marks the 25th anniversary of the first Annual Review of Immunology article to describe features of the T cell antigen receptor (TCR). In celebration of this anniversary, we begin with a brief introduction outlining the chronology of the earliest studies that established the basic paradigm for how the engaged TCR transduces its signals. This review continues with a description of the current state of our understanding of TCR signaling, as well as a summary of recent findings examining other key aspects of T cell activation, including cross talk between the TCR and integrins, the role of costimulatory molecules, and how signals may negatively regulate T cell function.

T cell activation.

Several members of the tumor necrosis factor receptor (TNFR) family function after initial T cell activation to sustain T cell responses. This review focuses on CD27, 4-1BB (CD137), OX40 (CD134), HVEM, CD30, and GITR, all of which can have costimulatory effects on T cells. The effects of these costimulatory TNFR family members can often be functionally, temporally, or spatially segregated from those of CD28 and from each other. The sequential and transient regulation of T cell activation/survival signals by different costimulators may function to allow longevity of the response while maintaining tight control of T cell survival. Depending on the disease condition, stimulation via costimulatory TNF family members can exacerbate or ameliorate disease. Despite these complexities, stimulation or blockade of TNFR family costimulators shows promise for several therapeutic applications, including cancer, infectious disease, transplantation, and autoimmunity.

Tnf/tnfr family members in costimulation of t cell responses

In the past 10 years, much has been learned about the biology of the inhibitor of apoptosis protein survivin and its expression and roles in cancer. Does survivin function as a nodal protein in cancer networks, and does this make it a promising therapeutic target?

http://dipbsf.uninsubria.it/monti/BFPN%202009/survivin.pdf

Survivin, cancer networks and pathway-directed drug discovery.

OX40 (CD134) and its binding partner, OX40L (CD252), are members of the TNFR/TNF superfamily and are expressed on activated CD4 and CD8 T cells as well as a number of other lymphoid and non-lymphoid cells. Costimulatory signals from OX40 to a conventional T cell promote division and survival, augmenting the clonal expansion of effector and memory populations as they are being generated to antigen. OX40 additionally suppresses the differentiation and activity of Treg, further amplifying this process. OX40 and OX40L also regulate cytokine production from T cells, antigen-presenting cells, NK cells, and NKT cells, and modulate cytokine receptor signaling. In line with these important modulatory functions, OX40/OX40L interactions have been found to play a central role in the development of multiple inflammatory and autoimmune diseases, making them attractive candidates for intervention in the clinic. Conversely, stimulating OX40 has shown it to be a candidate for therapeutic immunization strategies for cancer and infectious disease. This review provides a broad overview of the biology of OX40, and the intracellular signals from OX40, that impact many aspects of immune function, and have promoted OX40 as one of the most prominent costimulatory molecules known to control T cells.

The Significance of OX40 and OX40L to T cell Biology and Immune Disease

https://www.cell.com/immunity/pdf/S1074-7613(05)00107-X.pdf

Sustained survivin expression from OX40 costimulatory signals drives T cell clonal expansion.

Naive CD4 T cells can develop into regulatory T cells by acquiring the transcription factor Foxp3. Combined signals from the TCR, CD28, IL-2R, and TGF-βR promote Foxp3 expression in activated naive CD25− CD4 T cells. Here we show that OX40 (CD134) signaling inhibits TGF-β-driven Foxp3 mRNA and suppresses the conversion of naive Ag-specific transgenic CD4 T cells into CD25+Foxp3+ T cells. These data identify OX40 as a negative regulator of Foxp3 and suggest that OX40 can concomitantly promote effector T cell generation while antagonizing the differentiation of adaptive Foxp3+ regulatory T cells.

Cutting Edge: OX40 Inhibits TGF-β- and Antigen-Driven Conversion of Naive CD4 T Cells into CD25+Foxp3+ T cells

Immune regulation and control of regulatory T cells by OX40 and 4-1BB

CD28-deficient T cells arrest at the G1-S transition of the cell cycle. Here we show that this is controlled by the kinase aurora B, which exists in a complex with survivin and mammalian target of rapamycin (mTOR). Expression of aurora B in Cd28-/- T cells augmented phosphorylation of mTOR substrates, expression of cyclin A, hyperphosphorylation of retinoblastoma protein and activation of cyclin-dependent kinases 1 and 2 and promoted cell cycle progression. Interleukin 2 enhanced aurora B activity, and inactive aurora B prevented interleukin 2-induced proliferation. Moreover, expression of aurora B restored Cd28-/- T cell proliferation and promoted inflammation in vivo. These data identify aurora B, along with survivin and mTOR, as a regulator of the G1-S checkpoint in T cells.

Takanori So

Papers

The Significance of OX40 and OX40L to T cell Biology and Immune Disease

Sustained survivin expression from OX40 costimulatory signals drives T cell clonal expansion.

Cutting Edge: OX40 Inhibits TGF-β- and Antigen-Driven Conversion of Naive CD4 T Cells into CD25+Foxp3+ T cells

Immune regulation and control of regulatory T cells by OX40 and 4-1BB

The kinases aurora B and mTOR regulate the G1-S cell cycle progression of T lymphocytes.