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T-cell function is tightly regulated in order to prevent inappropriate activation or collateral damage during productive immune responses. One of the critical cell intrinsic regulatory elements is a series of inhibitory cell surface receptors. In normal immune responses, the integration of signaling from the T-cell receptor (signal 1), costimulatory and coinhibitory receptors (signal 2), and further signals provided by cytokines (signal 3) determine cell fate and activation status. Lack of appropriate stimulatory elements or an abundance of inhibitory signals can drive anergy or exhaustion, preventing the immune system from responding to foreign antigens, particularly those presented chronically such as cancer neoantigens. Multiple elements of this rheostatic system are therefore potentially targetable to enhance immunity for therapeutic benefit. Drugs targeting the inhibitory signaling pathway checkpoints (checkpoint inhibitors) have shown efficacy in several human cancers, including hematologic malignancies, forming the basis for the award of the Nobel Prize for Medicine in 2018 to James P. Allison and Tasuku Honjo “for their discovery of cancer therapy by inhibition of negative immune regulation.” Insights into the pathways most relevant for immune evasion in specific cancers have underpinned significant clinical progress and offer promising areas for future research, often in combination with other therapeutic modalities.

Acronyms and Abbreviations

aGvHD, acute graft-versus-host disease; ADCC, antibody dependent cellular cytotoxicity; APC, antigen presenting cell; ASCT, autologous stem cell transplantation; ATLL, adult T-cell leukemia/lymphoma; BCR, B cell receptor; cHL, classical Hodgkin Lymphoma; BV, brentuximab vedotin; CAR, chimeric antigen receptor; cHL, classical Hodgkin lymphoma; CPI, checkpoint inhibitors; CR, complete response; CTLA-4, cytotoxic T-lymphocyte-associated protein 4; DC, dendritic cell; DLBCL, diffuse large B-cell lymphoma; EBV, Epstein–Barr virus; FDA, Food and Drug Administration; GITR, glucocorticoid-induced tumor necrosis factor receptor; GvHD, graft versus host disease; HRS, Hodgkin and Reed-Sternberg; HLA, human leucocyte antigen; HTLV-1, human T-cell lymphotropic virus type 1; IL-2, interleukin-2; IRAE, immune-related adverse event; JAK2, Janus kinase 2; KIR, Killer-cell immunoglobulin-like receptor; LAG-3, lymphocyte-activation gene 3; LMP, latent membrane protein; MHC, major histocompatibility complex; NHL, non-Hodgkin lymphoma; NKT, natural killer T cells; ORR, objective response rate; PD-1, programmed cell death protein 1; PD-L1, programmed death-ligand 1; PD-L2, programmed death-ligand 2; PMBCL, primary mediastinal B cell lymphoma; TIM, T-cell immunoglobulin and mucin domain; TCR, T-cell receptor; TE, effector T cell; TIL, tumor-infiltrating lymphocyte; TMB, tumor mutational burden; TNeAB, tumor neo-antigen burden; TREG, regulatory T cell.


Immune checkpoints represent one of the most promising therapeutic targets for amplifying antitumor immune responses in patients with cancer. They consist of an array of inhibitory pathways that are crucial for maintaining self-tolerance and modulating the duration and amplitude of physiological immune responses. Tumors subvert some of these inhibitory pathways as a major mechanism of immune resistance, particularly to suppress tumor antigen–specific T-cell responses. Although there is an extended array of receptors that exert inhibitory effects, the two that are most advanced in terms of development of targeted therapeutics are ...

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