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OX40 (CD134) and OX40 ligand, important immune checkpoints in cancer

Authors Deng J, Zhao S, Zhang X, Jia K, Wang H, Zhou C, He Y 

Received 2 May 2019

Accepted for publication 30 July 2019

Published 6 September 2019 Volume 2019:12 Pages 7347—7353

DOI https://doi.org/10.2147/OTT.S214211

Checked for plagiarism Yes

Review by Single anonymous peer review

Peer reviewer comments 2

Editor who approved publication: Professor Gaetano Romano



Juan Deng,1,2 Sha Zhao,1,2 Xiaoshen Zhang,1,2 Keyi Jia,1,2 Hao Wang,1,2 Caicun Zhou,1 Yayi He1

1Department of Medical Oncology, Shanghai Pulmonary Hospital, Tongji University Medical School Cancer Institute, Tongji University School of Medicine, Shanghai 200433, People’s Republic of China; 2Medical School, Tongji University, Shanghai 200092, People’s Republic of China

Correspondence: Caicun Zhou; Yayi He
Department of Medical Oncology, Shanghai Pulmonary Hospital, Tongji University Medical School Cancer Institute, Tongji University School of Medicine, No. 507 Zhengmin Road, Shanghai 200433, People’s Republic of China
Tel +86 216 511 5006
Email [email protected][email protected]

Abstract: Immunotherapy has shown promising results in cancer treatment. Research shows that most patients might be resistant to these therapies. So, new immune therapies are needed. OX40 (CD134) and OX40 ligand (OX40L), costimulatory molecules, express on different types of immune cells. The interaction between OX40 and OX40L (OX40/OX40L) induces the expansion and proliferation of T cells and decreases the immunosuppression of regulatory T (Treg) cells to enhance the immune response to the specific antigen. For the important role OX40 takes in the process of immunity, many clinical trials are focusing on OX40 to find out whether it may have active effects in clinical cancer treatment. The results of clinical trials are still not enough. So, we reviewed the OX40 and its ligand (OX40L) function in cancer, clinical trials with OX40/OX40L and the correlation between OX40/OX40L and other immune checkpoints to add more ideas to tumor feasible treatment.

Keywords: cancer, immune checkpoints, OX40/OX40L, immunotherapy

Immunotherapy has shown promising results in cancer treatment,1 cancer immune checkpoint blockades also have got good results.25 It was demonstrated that combining cancer vaccines or checkpoint inhibitors with different immunotherapeutic agents could augment the anti-tumor effects and get better results in cancer patients.6,7

Tumor necrosis factor receptor superfamily member 4 (OX40) (CD134) and OX40 ligand (OX40L) (CD134L) (CD252) are on chromosome 1. The OX40 and OX40L could be expressed by endothelial cells, mast cells, activated natural killer (NK) cells, dendritic cells (DCs), B cells, microglial cells, activated T cells and Foxp3+ regulatory T cells.810 OX40L could initiate OX40 signals in activated T cells. OX40L on T cells could provide signals via the interactions between T cells and upregulate the anti-apoptotic protein on T cells to enhance T cell survival, cytokine production and induce the CD4 memory T cell expansion.1116 The co-stimulation in B cells through the OX40/OX40L pathway contributed to CD4 cell generation, survival and T helper 2 (Th2) development.17 OX40/OX40L could promote NK cell activation, cytokine production and cytotoxicity and enhance targeted cells lysis.18,19 Mast cell via the OX40/OX40L pathway could induce T cell proliferation.20,21 OX40 on Treg cells played an important role in Treg cell development and homeostasis.22,23 We made a figure to clarify the function of OX40-OX40L pathway (Figure 1).

Figure 1 OX40–OX40L interaction model.Abbreviations: Th2, T helper 2; NK, natural killer; TCR, T cell receptor; MHC, major histocompatibility complex; APC, antigen presenting cell.

OX40/OX40L and diseases

Many diseases were associated with OX40/OX40L, so many researchers focused on it to find new way of treatment. The activation of OX40 promoted the generation and expansion of activated T cells and memory T cells, thus aggravating autoimmune diseases like Graves’ disease, autoimmune arthritis and uveitis.2427 OX40 was critically important in sustaining the anti-viral immune response during the viral infection.19,2830 OX40–OX40L signaling increased the adaptive immune response to an allograft by promoting effector and memory T cell survival. And blockade of OX40–OX40L interaction could decrease the T cells infiltration in the targeted organs to prevent allograft rejection.3134 OX40L could promote the inflammatory cells infiltration into lesional tissues, leading to the pathological fibrosis in skin and internal organs. And blocking OX40–OX40L regressed the fibrosis.35,36 OX40–OX40L interaction on immune cells might contribute to idiopathic inflammatory myopathies through different pathways in the inflamed muscle.37 OX40/OX40L pathway was involved in the pathological process of Crohn’s disease (CD). And blockade anti-OX40 might be beneficial for the treatment by controlling the T cell-mediated inflammatory in vivo.38,39 Data implicated that OX40/OX40L participated in pathophysiology of acute myeloid leukemiaand also enhanced NK cell cytotoxicity.18

OX40/OX40L and cancer

OX40 was expressed on the tumor-infiltrating lymphocytes (TIL) in head and neck squamous cell carcinoma, ovarian cancer, gastric cancer, cutaneous squamous cell carcinoma, breast cancer and colorectal cancer.4045 Agonistic anti-OX40 antibodies had anti-tumor effects.4652 OX40 triggering regressed Treg cells, allowing DCs to reach the draining lymph nodes and prime the specific CD8 lymphocytes response to the tumor.48,53 Many research focused on the anti-tumor immunotherapy, based on activating costimulatory molecules OX40 and OX40L. Here, we showed some of them (Table 1).

Table 1 OX40/OX40L and cancer

Clinical trials of OX40/OX40L

Based on the role of OX40 and OX40L in the immune system, more and more research focused on its therapeutic effects. Many companies detected the immune checkpoints OX40 and OX40L, searching for the new approaches to treat tumors and autoimmune diseases, many of which are now making great advance in clinical development (Table 2). The results of clinical trials showed the OX40, as a potent immune-stimulating target, played an important role in anti-tumor therapy. The agonist anti-OX40 increased CD4 FoxP3 and CD8 T cells proliferation and the response to the tumor-specific antigen, enhancing both humoral and cellular immunity in cancer treatment.49

Table 2 Clinical trials with anti-OX40

Correlation of OX40/OX40L and other immune checkpoints

The results of studies suggested that some diseases were not sensitive to antibody therapy alone. So, it was necessary to study on the relationship between checkpoints to work out more effective treatment. CTLA-4, a molecule on T cells, inhibited the proliferation of T cells and cytokine production, thus limiting the lymphocyte immune reaction.6872 Anti-CTLA-4 blockade induced the depletion of Treg cells within tumor and activation of Teff cells.71,7376 Combining agonist anti-OX40 and antagonist anti-CTLA-4 further enhanced CD4 and CD8 T cells responses to antigen, indicating they had synergistic effects in improving tumor regression.7779 And the cytokine of Th1 and Th2 CD4 T cells increased significantly.64 Whether the combination therapy altered the suppressive function of Treg cells remained deeper exploration.63,64 The combination was still more than the sum of its part.80

Programmed death-1 (PD-1) is a molecule that suppresses the immune reaction, inducing T cell exhaustion and apoptosis. Programmed death-ligand 1 (PD-L1), expressed on tumor cells or other tumor-related immune cells, could suppress anti-tumor immune response.8184 The function of PD-1 and PD-L1 was affected by the complex immunoregulation. PD-1 blockade had already been used in cancer treatment and got a satisfying result.82,84 It was reported that PD-1 inhibitor added at the initiation of the cancer treatment could reduce the effects of OX40 agonist antibody, for it might cause the antigen-specific CD8+ T cell diminishment.85 And timing of PD-1 blockade using might determine whether it was effective immunotherapy when combined with OX40 therapy.81 In most cases, OX40 agonist and PD-1 blockade had a synergistic effect in disease treatment. OX40, combined with CD27 mediated co-stimulation, could synergize with PD-L1 inhibitor by activating CD8+ T cells.86 Combining OX40 stimulation and PD-L1 blockade could synergistically augment hepatitis B virus (HBV)-specific CD4 T cell responses by promoting Th cells to secrete IFN-γ and IL-21 in patients with HBV infection.87 In some poorly immunogenic tumors, combining PD-1 blockade and OX40 stimulation had an anti-tumor effect by inducing cytotoxic T lymphocyte, increasing the Teff cells and decreasing the immunosuppressive cells, while individual did not.41

4-1BB (CD137), member of the TNFR family enhanced T cell proliferation, effector function and cytokines production, and induced maturation of DC, thus increasing the immune reaction.8893 Agonistic anti- 4-1 BB increased the TIL within tumor and upregulated the expression of 4-1 BB on the immune cells, augmenting anti-tumor reaction.90,94,95 The costimulatory pathway of OX40–OX40L and 4-1 BB-4-1 BBL functioned independently to enhance immune cells response.88 The combination of OX40 agonist and 4-1BB agonist induced profound expansion of CD8 T cell.96,97 But the response of CD4 T cell to the dual costimulation seemed to be additive instead of synergistic.98 On the whole, the combination therapy could synergistically inhibit cancer by producing more enhanced signals.98,99

Summary

Immune checkpoints play vital roles in cancer treatment. It was proved that the agonist anti-OX40/OX40L could enhance anti-tumor response by promoting the function of immune cells. More and more researchers focused on OX40/OX40L in cancer immunotherapy. But until now, the effects of OX40/OX40L treatment are still limited. Researchers are devoted to combine OX40/OX40L with other immune checkpoints in cancer treatment, which had also made some achievements, but the mechanisms of the synergy between OX40/OX40L and other immune checkpoints still need to be further studied.

Acknowledgment

This study was supported in part by grants from National Natural Science Foundation of China (81802255), Shanghai Pujiang Program (17PJD036), Shanghai Municipal Commission of Health and Family Planning Program (20174Y0131), National Key Research & Development Project (2016YFC0902300), Major Disease Clinical Skills Enhancement Program of three year action plan for promoting clinical skills and clinical innovation in municipal hospitals, Shanghai Shen Kang Hospital Development Center Clinical Research Plan of SHDC (16CR1001A),“Dream Tutor" Outstanding Young Talents Program (fkyq1901), Key Disciplines of Shanghai Pulmonary Hospital (2017ZZ02012), and Shanghai Science and Technology Commission (16JC1405900).

Disclosure

The authors report no conflicts of interest in this work.

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