CD137+ T-Cells: Protagonists of the Immunotherapy Revolution

Abstract

The CD137 receptor (4-1BB, TNF RSF9) is an activation induced molecule expressed by antigen-specific T-cells. The engagement with its ligand, CD137L, is capable of increasing T-cell survival, proliferation, and cytokine production. This allowed to identify the CD137+ T-cells as the real tumor-specific activated T-cell population. In fact, these cells express various TCRs that are specific for a wide range of tumor-derived peptides, both shared and neoantigenic ones. Moreover, their prevalence in sites close to the tumor and their unicity in killing cancer cells both in vitro and in vivo, raised particular interest in studying their potential role in different strategies of immunotherapy. They indeed showed to be a reliable marker able to predict patient’s outcome to immune-based therapies as well as monitor their response. In addition, the possibility of isolating and expanding this population, turned promising in order to generate effector antitumor T-cells in the context of adoptive T-cell therapies. CD137-targeting monoclonal antibodies have already shown their antitumor efficacy in cancer patients and a number of clinical trials are thus ongoing to test their possible introduction in different combination approaches of immunotherapy. Finally, the intracellular domain of the CD137 receptor was introduced in the anti-CD19 CAR-T cells that were approved by FDA for the treatment of pediatric B-cell leukemia and refractory B-cell lymphoma.

Immune effects of CDK4/6 inhibitors in patients with HR+/HER2− metastatic breast cancer: Relief from immunosuppression is associated with clinical response

“…In addition, the CD3 + CD137 + cell subset was analysed, as these cells are regarded as anti-tumour effector T cells. 22 During CDK4/6i treatment, a trend of increased CD137 expression was observed for CD3 + cells ( p =0.07), but most importantly, CD8 + CD137 + cell levels significantly increased ( p <0.01). These results suggest that CDK4/6i treatment favours the overall activation of both subsets of CD3 + effector cells involving distinct co-stimulatory mechanisms.…”

“…Recently, CD3 + CD137 + T cells have been shown to play a fundamental role in efficacious anti-tumour immunity. The CD137 receptor (4-1BB, TNFRSF) is a member of the tumour necrosis factor receptor (TNFR) family that has a tumour-specific activation function 22 and is expressed by CD8 + and CD4 + T cells upon activation. Indeed, these cells have attracted particular interest regarding their potential role in various immunotherapy strategies owing to their unique ability to kill tumour cells.…”

The Effect of the Nanoparticle Shape on T Cell Activation

“…CD137 + CD8 + T cells are believed to be the tumor‐infiltrating lymphocytes (T TIL ) population that promises the better clinical outcome. [ 38 ] Isolation and ex vivo expansion of the CD137 + , CD8 + T cell population is adopted in clinical trial as a promising strategy that enhances the efficacy of the adoptive T cell transfer against metastatic melanoma. [ 39 ] To test if our platform can promote generation of CD137 + CD8 + T cells, we first cultured the CD8 + T cells on AR1 or AR7 substrate for 6 days, then the obtained T cells were co‐cultured with human cervical carcinoma (HeLa cells) in a regular culture dish for another 7 days.…”

“…CD137 expression on CD8 + T cells is considered as tumor infiltrating lymphocytes acquiring the effector T cells phenotype and promises the better clinical outcome. [38][39][40] Isolation and ex vivo expansion of the CD137 + , CD8 + T cell population is a key to enhance the efficacy of the adoptive T cell transfer. [39] Finally, up-regulated expression of CD137 on CD8 + T cells co-cultured with human cervical carcinoma demonstrated a great potential of the AuNR platform for activation and ex vivo expansion of T cells.…”

Circulating Exhausted PD-1+CD39+ Helper CD4 T Cells Are Tumor-Antigen-Specific and Predict Response to PD-1/PD-L1 Axis Blockade

“…In addition, we showed that CD39 + memory Tconv TILs, like circulating CD39 + memory Tconv, contained high proportions of CD28 + cells. CD137 receptor, upregulated in T cells following activation [ 30 ], was associated, when expressed in CD8 and CD4 TILs, with clinical response to ICB [ 31 ]. In the circulation, CD137 expression in CD8, but not in CD4 T cells, was predictive of clinical responses [ 31 , 32 ].…”