[The "immune checkpoints", how does it work].

Costimulatory molecules allow the full lymphocyte activation, whereas co-inhibitory molecules are negative counterparts that act as immune regulators, avoiding excessive response. In some context of chronic inflammation such as cancer, co-inhibitory immune checkpoint as CTLA-4, PD-1, Lag-3, Tim-3 can accumulate at the membrane of T cells leading to a state of anergy and therefore the loss of tumor growth control. Consequently, these immune checkpoints are considered as potential target in the treatment of cancer. Immunotherapy by anti-CTLA-4 and anti-PD-1/PD-L1 early demonstrated very good proof of efficacy in the setting of several cancers types, supporting the role of these molecules in tumor immune escape. The aim of this review is to summarize the pathophysiology of immune checkpoints and their therapeutic applications in cancer.

Granier C ，Soumelis V ，Mandavit M ，Gibault L ，Belazzoug R ，de Guillebon E ，Badoual C ，Tartour E ，Roussel H ... -  《ANNALES DE PATHOLOGIE》

T cell checkpoint regulators in the heart.

T lymphocyte-mediated immune responses in the heart are potentially dangerous because they can interfere with the electromechanical function. Furthermore, the myocardium has limited regenerative capacity to repair damage caused by effector T cells. Myocardial T cell responses are normally suppressed by multiple mechanisms of central and peripheral tolerance. T cell inhibitory molecules, so called immune checkpoints, limit the activation and effector function of heart antigen-reactive T cells that escape deletion during development in the thymus. Programmed cell protein death-1 (PD-1) and cytotoxic T-lymphocyte-associated protein-4 (CTLA-4) are checkpoint molecules homologous to the costimulatory receptor CD28, and they work to block activating signals from the T cell antigen receptor and CD28. Nonetheless, PD-1 and CTLA-4 function in different ways and at different steps in a T cell response to antigen. Studies in mice have established that genetic deficiencies of checkpoint molecules, including PD-1, PD-L1, CTLA-4, and lymphocyte activation gene-3, result in enhanced risk of autoimmune T cell-mediated myocarditis and increased pathogenicity of heart antigen-specific effector T cells. The PD-1/PD-L1 pathway appears to be particularly important in cardiac protection from T cells. PD-L1 is markedly up-regulated on myocardial cells by interferon-gamma secreted by T cells and PD-1 or PD-L1 deficiency synergizes with other defects in immune regulation in promoting myocarditis. Consistent with these studies, myocarditis has emerged as a serious adverse reaction of cancer therapies that target checkpoint molecules to enhance anti-tumour T cell responses. Histopathology and immunohistochemical analyses of myocardial tissue from immune checkpoint blockade (ICB)-treated patients echoes findings in checkpoint-deficient mice. Many questions about myocarditis in the setting of cancer immunotherapy still need to be answered, including the nature of the target antigens, genetic risk factors, and variations in the disease with combined therapies. Addressing these questions will require further immunological analyses of blood and heart tissue from patients treated with ICB.

Grabie N ，Lichtman AH ，Padera R 《-》

[Predictive biomarkers of efficacy of checkpoint blockade inhibitors in cancer treatment].

The remarkable efficacy of PD-1/PD-L1 and CTLA4 immune checkpoint inhibitors has led to numerous approvals in melanoma, non-small cell lung cancer, kidney cancer and several other cancers. Nevertheless, a response is observed in a variable proportion of patients, emphasizing the need for predictive biomarkers of efficacy of immune checkpoint inhibitors effectiveness. Several predictive biomarkers of efficacy are of interest: companion tests such PD-L1 immunohistochemistry, the mutational load, the immune status of the tumor and its molecular profile. They do not allow a perfect selection of the patients, but standardization procedures for certain techniques are ongoing. Moreover the emergence of new approaches, such as the multiplex in situ techniques and the microbiote analysis, may offer the opportunity to better select patients who really benefit from immunotherapy. The goal of this article is to discuss available and promising predictive biomarkers of efficacy for immunotherapy strategies.

Duruisseaux M ，Lize-Dufranc C ，Badoual C ，Bibeau F ... -  《ANNALES DE PATHOLOGIE》

Immune checkpoint inhibitors.

Hui E 《-》

Can Immunogenic Chemotherapies Relieve Cancer Cell Resistance to Immune Checkpoint Inhibitors?

Rivera Vargas T ，Apetoh L 《Frontiers in Immunology》