T cell–encoded CD80 and 4-1BBL induce auto- and transcostimulation, resulting in potent tumor rejection

Abstract

To reject tumors, T cells must overcome poor tumor immunogenicity and an adverse tumor microenvironment. Providing agonistic costimulatory signals to tumor-infiltrating T cells to augment T cell function remains a challenge for the implementation of safe and effective immunotherapy. We hypothesized that T cells overexpressing selected costimulatory ligands could serve as cellular vehicles mediating powerful, yet constrained, anatomically targeted costimulation. Here, we show that primary human T cells expressing CD80 and 4-1BB ligand (4-1BBL) vigorously respond to tumor cells lacking costimulatory ligands and provoke potent rejection of large, systemic tumors in immunodeficient mice. In addition to showing costimulation of bystander T cells (transcostimulation), we show the effect of CD80 and 4-1BBL binding to their respective receptors in the immunological synapse of isolated single cells (autocostimulation). This new strategy of endowing T cells with constitutively expressed costimulatory ligands could be extended to other ligand-receptor pairs and used to enhance any targeted adoptive transfer therapy.

Infiltrating CTLs in Human Glioblastoma Establish Immunological Synapses with Tumorigenic Cells

“…Importantly, recent experimental studies performed in mice have demonstrated that the stimulation of IS formation results in a potent tumor rejection involving GzmB polarization. 44 The demonstration here that CD8 ϩ T cells establish GzmB-mediated IS with tumorigenic cells in human GBM points the way toward strategies for tumor immunotherapy and identifies potential molecular targets, [45][46][47] which will permit the stimulation of CTL synapse formation.…”

Adoptive immunotherapy using human peripheral blood lymphocytes transferred with RNA encoding Her-2/neu-specific chimeric immune receptor in ovarian cancer xenograft model

“…Even if T cells are generated with high avidity for antigens, the success of adoptive T-cell immunotherapy cannot be guaranteed because of uncertainty of its persistency and reactivity in vivo. 4 The genetic modification of T-cell function allowed naı¨ve T cells transformed into tumor-reactive effector cells harboring high affinity T-cell receptors (TCRs) as well as chemokine and cytokine receptors that enhance their survival and homing properties. 5 Rosenberg and co-workers 6 reported from the first clinical trial that 2 out of 16 patients, who received autonomous lymphocytes expressing MART-1 TCR, underwent regression of liver and lung helium metastases and showed complete regression over 2 years later.…”

Chimeric antigen receptor modified T cell therapy for B cell malignancies

“…In addition to improvements in CAR design, other approaches have been investigated to improve CAR-modified T cell function and persistence. While costimulation has most often been incorporated within the CAR construct, T cell function can be augmented by provision of costimulation in formats that do not include the costimulatory domain within the CAR [42]. Engineering T cells to express both the CAR and costimulatory molecule ligands such as CD80 or CD86 may ensure delivery of a costimulatory signal to adoptively transferred T cells in the absence of tumor-derived costimulation [42].…”

“…While costimulation has most often been incorporated within the CAR construct, T cell function can be augmented by provision of costimulation in formats that do not include the costimulatory domain within the CAR [42]. Engineering T cells to express both the CAR and costimulatory molecule ligands such as CD80 or CD86 may ensure delivery of a costimulatory signal to adoptively transferred T cells in the absence of tumor-derived costimulation [42]. Another approach involves modifying T cells to express both a firstgeneration CAR and a separate chimeric receptor that contains a distinct extracellular antigen-binding domain and a costimulatory domain, but no CD3f signaling domain (Fig.…”