免疫チェックポイント阻害剤：がんを克服するための戦略か？

Our immune system is constantly on the lookout for pathogens and, once it encounters one, it mounts a strategic attack to fight it: it is the so-called immune response. To minimize the potential collateral damage to healthy cells and tissues though, this response needs to be tuned down.^{(1, 2)} And that is precisely the role of inhibitory immune checkpoints, a plethora of molecules naturally expressed both on T cells and antigen-presenting cells that maintains self-tolerance and limits tissue damage by recognizing ligands expressed on self-tissues.⁽³⁾ In the past 30 years, a broad range of immune checkpoint molecules have been identified, including cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) and programmed cell death protein 1 (PD-1) whose discoveries have earned James P. Allison and Tasuku Honjo the Nobel Prize in medicine in 2018. Both proteins act as negative regulators of T cell activation, thereby preventing unwanted immune responses.^{(4, 5, 6, 7, 8)}

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Immune checkpoints are also expressed on many tumor cells, allowing them to cleverly evade host immune response and divide uncontrollably.⁽⁹⁾ Interestingly, several in vivo studies have demonstrated that antibodies directed against key immune checkpoints such as PD-1 and CTLA-4 inhibit their function, thereby allowing the elimination of certain tumor cells.^{(2, 10, 11, 12)} These findings have provided a rationale for targeting immune checkpoints to enhance antitumor immunity, and revolutionized cancer therapy. Indeed, several immune checkpoint molecules, including PD-1 and CTLA-4, have been approved by the Food and Drug Administration (FDA) for treating certain types of cancers, while others are under clinical trials.⁽¹²⁾ These new immunotherapies, known as checkpoint inhibitors, represent a highly effective treatment for solid cancers, such as metastatic melanomas, non-small-cell lung carcinomas and liver cancer, and offer patients a durable remission from diseases whose outcomeswere previously invariably terminal.^{(12, 13, 14)}

Accumulating evidence suggests that only a number of patients benefit from checkpoint inhibitors, and that a fraction of those develop a wide range of severe autoimmune responses.^{(3, 13, 15, 16)} These observations have given rise to the need to develop predictive biomarkers to differentiate between responders and non-responders, avoid any adverse effect, and facilitate the decision-making process to select the best immune checkpoint inhibitor-based therapy for each patient.^{(12, 17)} Ongoing clinical studies have already identified some of them (e.g., immune cell counts, neoantigens, gene mutations)⁽¹²⁾ and others are underway, which could represent an important first step toward personalized medicine in cancer treatment.

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参考文献：

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4. Linsley PS, Ledbetter JA (1993) The role of the CD28 receptor during T cell responses to antigen. Annu Rev Immunol 11: 191.
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11. Selby M, Englehardt J, Lu L-S, Quigley M, Wang C, Chen B, Korman AJ (2013) Antitumor activity of concurrent blockade of immune checkpoint molecules CTLA-4 and PD-1 in preclinical models. J Clin Oncol 31 (suppl; abstr 3061).
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