Immune Netw.  2014 Dec;14(6):265-276. 10.4110/in.2014.14.6.265.

The CD28-B7 Family in Anti-Tumor Immunity: Emerging Concepts in Cancer Immunotherapy

• Leung J
• Suh WK

• KMID: 2150817
• DOI: http://doi.org/10.4110/in.2014.14.6.265

Abstract

The interactions between B7 molecules and CD28-family receptors are crucial in the regulation of adaptive cellular immunity. In cancer, the aberrant expression of co-inhibitory B7 molecules has been attributed to reduced anti-tumor immunity and cancer immune evasion, prompting the development of cancer therapeutics that can restore T cell function. Murine tumor models have provided significant support for the targeting of multiple immune checkpoints involving CTLA-4, PD-1, ICOS, B7-H3 and B7-H4 during tumor growth, and clinical studies investigating the therapeutic effects of CTLA-4 and PD-1 blockade have shown exceptionally promising results in patients with advanced melanoma and other cancers. The expression pattern of co-inhibitory B7 ligands in the tumor microenvironment has also been largely correlated with poor patient prognosis, and recent evidence suggests that the presence of several B7 molecules may predict the responsiveness of immunotherapies that rely on pre-existing tumor-associated immune responses. While monotherapies blocking T cell co-inhibition have beneficial effects in reducing tumor burden, combinatorial immunotherapy targeting multiple immune checkpoints involved in various stages of the anti-tumor response has led to the most substantial impact on tumor reduction. In this review, we will examine the contributions of B7- and CD28-family members in the context of cancer development, and discuss the implications of current human findings in cancer immunotherapy.

Keyword

B7 family; CD28 family; Co-stimulation; Co-inhibition; Cancer immunotherapy; Immune evasion

MeSH Terms

B7 Antigens
Humans
Immune Evasion
Immunity, Cellular
Immunotherapy*
Ligands
Melanoma
Prognosis
Tumor Burden
Tumor Microenvironment
B7 Antigens
Ligands

Figure

• 

  Figure 1 Interactions between co-stimulatory and co-inhibitory B7 and CD28 family members. B7 family ligands belong to the immunoglobulin superfamily and contain immunoglobulin-V-like and immunoglobulin-C-like domains. B7-1 and B7-2 are expressed on APCs, and function primarily to regulate the initial T cell priming by engaging CD28 or CTLA-4 receptors found on naïve and activated T cells, respectively. The expression of other B7 ligands is not limited to APCs, and is also found in non-lymphoid organs. ICOSL, PD-L1, PD-L2, B7-H3 and B7-H4 signaling mediate peripheral tolerance, and their expression in cancer have been predictive of patient prognosis. CD28 family receptors are also part of the immunoglobulin superfamily, but consist of a lone immunoglobulin-V-like domain. CD28 and CTLA-4 compete for B7-1 and B7-2 during early stages of T cell response, whereas the engagement of ICOS to ICOSL, and of PD-1 to PD-L1/PD-L2 mediate the function of pre-activated T cells. To date, the receptors for B7-H3 and B7-H4 remain unidentified, although several candidates have been proposed. In addition to the canonical B7:CD28 signaling pathways, B7-1 has also been demonstrated to reverse signal upon PD-L1 engagement, adding to the complexity of how B7-mediated signals function during tumor growth. Receptors with established T cell co-stimulatory functions are in red; those with co-inhibitory roles in blue.

• 

  Figure 2 Stages of the anti-tumor T cell response in which B7 and CD28 blockade may function. In the initial T cell priming phase, DCs migrate from the tumor microenvironment to draining lymph nodes and present tumor antigens to naïve T cells. During this process, co-stimulatory signals provided by B7-1 and B7-2 to CD28 receptors prevent T cell anergy. (1) CTLA-4 plays a significant role in diminishing CD28-mediated co-stimulation, and inhibition of CTLA-4 has been shown to enhance the expansion of T cells specific to tumor-associated antigens. (2) Following activation, effector T cells infiltrate into the tumor to exert their functions, yet a host of immunosuppressive factors (such as MDSCs and Tregs) can dampen the anti-tumor response. Tumor cells and Tregs routinely upregulate co-inhibitory molecules such as PD-L1, B7-H3, B7-H4 and CTLA-4, weakening T cell immunity. Abrogation of these pathways results in enhanced anti-tumor responses, whereas the engagement of ICOS on TILs may be required for the persistence of tumor-specific T cells. (3) Lastly, elevated PD-L1 on tumor and/or infiltrating immune cells leads to T cell exhaustion, which can be reversed by PD-1 or PD-L1 blockade. Combinatorial immunotherapies disrupting multiple immunosuppressive mechanisms are predicted to improve anti-tumor efficacy.

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