Costimulatory pathways occur via interactions between naive and/or activated T cells and their ligands on APCs. The costimulatory signals amplify and modify the original TCR activation signal and, in turn, activate and regulate T cell expansion and/or differentiation to translate the signal into an immune response or immune tolerance.
CD28 + CD80 (B7-1)
The second but primary signal of the costimulatory pathway involved in T cell activation occurs when CD28 on the T-cell surface binds to one or both of the B7 molecules, B7-1 (CD80) and B7-2 (CD86), on the APC. The combination of intracellular signals generated by the antigen receptor, coreceptor (CD4+ or CD8+) and costimulatory receptor CD28, initiates naive antigen-specific T cell activation and proliferation, as well as enhances production and secretion of inflammatory cytokines, including IL-2, IL-4 and IL-10. Increased expression of inflammatory cytokines, in turn, stimulates T cell differentiation into appropriate effector T cells based on the immunological insult. The CD28 signaling pathway also plays an important role in inhibiting T cell anergy, or absence of normal immune response, via cytokine-mediated enhancement of T cell proliferation. However, tumor evasion of the CD28/B7 stimulatory pathway has been shown to result in enhanced immunosuppression and poorer prognosis in patients with cancer.
CD28 co-stimulation is not only a key player in activation of T cells, but also T cell effector responses, differentiation, survival and migration to areas of infection and inflammation. They also play a vital role in the development and proliferation of regulatory T cells (Tregs) through the production of IL-2. Lastly, co-stimulation with B7 molecules, CD80/CD86, triggers NK cell-mediated cytotoxicity and is thought to play a role in NK cell activation, proliferation and cytokine secretion.
ICOS + CD275 (ICOS-L)
Inducible T cell co-stimulator (ICOS), a member of the CD28 family of immune receptors, is a stimulatory receptor expressed on the surface of activated CD4+ and CD8+ T cells and NK cells upon initiation of CD28 signaling. Its ligand, ICOSL, is expressed on APCs, including dendritic cells and macrophages. Following T cell activation, ICOS upregulation perpetuates the activation, proliferation, function and survival of cytotoxic T cells and the survival of memory T cells. Additionally, ICOS signaling plays a significant role in T cell-dependent B cell maturation. Upon recognition of specific pathogen, increases in helper T cells leads to enhanced inflammatory cytokine production, which, in turn, initiates B cell differentiation. The ICOS/ ICOS-L pathway has also been suggested to enhance the function of activated NK cells during the innate immune response. Recently, ICOS expression has been investigated as a useful predictive biomarker of response to checkpoint inhibitor treatments for cancer and could be an attractive target for combination immunotherapy. Research has shown combination immunotherapy that provides artificial stimulation of the ICOS pathway, along with inhibition of the CTLA-4 inhibitory pathway, enhances the immune response.
CD40 + CD40L
CD40, a member of the tumor necrosis factor (TNF) receptor family, is expressed by APCs and B cells. Its ligand, CD40L, is primarily expressed on helper T cells and other immune effector cells shortly following T cell activation. CD40-CD40L binding on activated T cells stimulates cytokine secretion from B cells, which subsequently enhances T cell activation and anti-tumor immunity. T cell activation then signals macrophages to increase expression of MHC II protein and B7, thereby further stimulating proliferation of helper T cells.
CD40 is often expressed in advanced tumors, and anti-CD40 antibodies have been shown to have promising effects in the treatment of myelomas and leukemia. CD40L expression is believed to indirectly effect anti-tumor activity by augmenting the anti-tumor response of B and T cells.
OX40L + OX40
OX40, another member of the TNF receptor family, is expressed on activated cytotoxic and Treg cells. Upon binding with its ligand (OX40L) on APCs, OX40 both activates and amplifies T cell responses by promoting T cell proliferation, function, survival and cytokine production. OX40 also aids in T cell differentiation into memory T cells. OX40 has been shown to inhibit the reproduction, immunosuppressive effects and suppressive function of Tregs on T cell activation, thereby aiding in the attenuation of autoimmune reactions. In addition to T cells, the OX40/OX40L pathway is also involved in NK cell activation, cytokine production, cytotoxicity and enhancement of NK’s cell lysis function. Studies have shown that OX40 plays a vital role in creating a more favorable antitumor immune response during the tumor microenvironment, thus explaining its utility in enhancing tumor free survival in cancer patients.
CD137L + CD137
CD137 binding to its ligand CD137L on CD8+ T cells leads to markedly enhanced activation, proliferation and survival of cytotoxic T lymphocytes. Stimulation of CD137 expression has been shown to play an important role in inhibition of autoimmune and inflammatory diseases mediated by CD4+ T cells. CD137L/CD137’s role in the inflammatory response is mediated through NK cells and its effects on myeloid cell differentiation and function as well as the induction of B cell proliferation and immunoglobulin production. Further understanding of CD137L/CD137’s roles in the inflammatory response and T cell immunity are key to its use in immunotherapy. Current therapies have shown inhibition of CD137 activates cytotoxic T cells and increases cytokine production, which are known to be critical for effective activation and regulation of the immune response.
SLAMF7 + SLAMF7 and activating adaptor protein
Signaling lymphocytic activation molecule family member 7 (SLAMF7) is an activating receptor expressed on NK cells and other immune cells, apart from solid tissues and hematopoietic stem cells. Activation of the SLAMF7 pathway is involved in the activation of NK cells’ natural cytotoxicity and rapid response against cancer and other diseases. SLAMF7 is known to stimulate both the innate and adaptive immune responses. Upon B cell activation, SLAMF7 expression is upregulated, resulting in B cell proliferation and production of autocrine cytokines (i.e. IL-14). SLAMF7 is a target for multiple myeloma immunotherapy due to its high expression pattern in multiple myeloma cells and lack of expression on healthy tissue, primary tumors and hematologic and nonhematologic cells. Moreover, SLAMF7 has the potential to serve as biomarker for multiple myeloma progression because its expression correlates with disease stage.
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