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Co-inhibitory B7-CD28 family member proteins negatively regulate T cell responses and are extensively involved in tumor immune evasion. Blockade of classical CTLA-4 (cytotoxic T lymphocyte-associated antigen-4) and PD-1 (programmed cell death protein-1) checkpoint pathways have become the cornerstone of anti-cancer immunotherapy. New inhibitory checkpoint proteins such as B7-H3, B7-H4, and BTLA (B and T lymphocyte attenuator) are being discovered and investigated for their potential in anti-cancer immunotherapy. In addition, soluble forms of these molecules also exist in sera of healthy individuals and elevated levels are found in chronic infections, autoimmune diseases, and cancers. Soluble forms are generated by proteolytic shedding or alternative splicing. Elevated circulating levels of these inhibitory soluble checkpoint molecules in cancer have been correlated with advance stage, metastatic status, and prognosis which underscore their broader involvement in immune regulation. In addition to their potential as biomarker, understanding their mechanism of production, biological activity, and pathological interactions may also pave the way for their clinical use as a therapeutic target. Here we review these aspects of soluble checkpoint molecules and elucidate on their potential for anti-cancer immunotherapy.

Antibody-based immunotherapies play a pivotal role in cancer research with efficient achievements in tumor suppression. Tumor survival is assisted by modulation of immune checkpoints to create imbalances between immune cells and cancer cell's environment. The modulation results in T-cell signal inhibition ultimately inert its proliferation and activation against various tumor cells. PD-L1, a 40 kDa transmembrane protein of B7 family, binds with PD-1 on the membrane of T cells which results in inhibition of T-cell proliferation and activation. PD-L1/PD-1 pathway has generated novel target sites for antibodies that can block PD-L1/PD-1 interactions.The blockage results in T-cell proliferation and tumor cell suppression. The PD-L1 immune checkpoint strategies' development, expression and regulations, signal inhibitions, and developmental stages of PD-L1/PD-1 antibodies are briefly discussed here in this review. All this information will provide a base for new therapeutic development against PD-L1 and PD-1 immune checkpoint interactions and will make available promising treatment options. K E Y W O R D Santibody, immune checkpoint, immunotherapy, PD-1, PD-L1

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