3.6 CD27 (TNF Receptor Superfamily Member 7)
CD27, also known as TNF receptor superfamily member 7 (TNFRSF7), is a co-stimulatory receptor expressed on various immune cells, normally expressed on CD4+ and CD8+ T cells, natural killer (NK) cells and thymocytes, and on memory B cells (primed B cells) [337]. CD27 is expressed on naive CD4+ and CD8+ T cells, while most other co-stimulatory TNFRs are produced only after T cell activation [338]. Its ligand, CD70 (CD27-L, TNFSF7), is primarily expressed on activated NK cells, APCs such as dendritic cells, and on some subsets of activated T (conventional- and regulatory T cells) and B cells. The interaction between CD27 and CD70 plays a critical role in regulating immune responses, particularly in promoting T cell activation and memory formation [339, 340].
When CD27 on T cells engages with CD70, it initiates signaling pathways that enhance T cell activation, survival, and effector function. This includes promoting T cell proliferation and cytokine production, such as interleukin-2 (IL-2), interferon-gamma (IFN-γ), and tumor necrosis factor-alpha (TNF-α) [337, 341, 342]. These cytokines are crucial for orchestrating effective immune responses against infections and tumors. In addition to its role in T cell activation, CD27 signaling also contributes to the generation and maintenance of memory T cells. Memory T cells are essential for providing long-lasting immune protection against previously encountered pathogens and tumors [337, 341, 342].
Preclinical research has shown that CD27 agonists can enhance tumor-specific T cell responses, promote tumor regression, and improve survival in animal models. Agonistic anti-CD27 antibodies in a murine model of melanoma, led to reduction in growth of lung metastases and subcutaneous tumors, due to  enhanced effector function and persistence, and reduced PD-1 expression of tumor infiltrating CD8(+) T cells [343]. In a study by Sakanishi et al. on mice with syngeneic T-cell lymphoma, a non-depleting agonistic mAb against CD27 demonstrated promise for cancer therapy by co-stimulating the induction of tumor-specific cytotoxic T lymphocytes (CTLs) [344]. A study by French et al. discovered that administering agonistic anti-CD27 mAbs without a DC maturation signal completely protected tumor-bearing mice, offering a highly potent method for enhancing antitumor T-cell immunity [345]. Yang et al. conducted a study showing that TanCAR-T cells, which target CD70 and B7-H3, displayed improved antitumor activity and addressed the issues of antigenic heterogeneity and variability across multiple tumor tissue samples [346].
The monoclonal antibody (mAb) targeting CD27, known as varlilumab (also referred to as CDX-1127 or 1F5), has progressed into clinical trials following promising results in preclinical studies [347, 348]. In transgenic mice expressing hCD27, the fully human IgG1 monoclonal antibody 1F5, which has agonist activity, effectively induced proliferation and cytokine production from hCD27-Tg-derived T cells when combined with TCR stimulation [348]. Early phase clinical trials have been done or are underway, for evaluating CD27 agonists either as monotherapy [NCT0146013440] [NCT0101591121] [NCT0221689044] [NCT0149782145] [NCT01813539+NCT0275925046] or in combination with other treatment modalities, including checkpoint inhibitors [NCT04081688] [NCT03038672], anti-CD20 monoclonal antibody, Rituximab [NCT03307746],  and chemotherapy [NCT04023526/ NCT04150887]. Fourth-generation CAR-T cell targeting CD70 is also undergoing clinical trials [NCT03125577]. The combination of CD27 agonists with checkpoint inhibitors, for example, aims to enhance the efficacy of immune checkpoint blockade by augmenting T cell activation and overcoming immunosuppressive mechanisms within tumors. Preliminary data from these trials show promising results (well tolerated with promising biological and early clinical activity) [349, 350].