Recent advances in immunotherapies: from infection and autoimmunity, to cancer, and back again

Abstract

For at least 300 years the immune system has been targeted to improve human health. Decades of work advancing immunotherapies against infection and autoimmunity paved the way for the current explosion in cancer immunotherapies. Pathways targeted for therapeutic intervention in autoimmune diseases can be modulated in the opposite sense in malignancy and infectious disease. We discuss the basic principles of the immune response, how these are co-opted in chronic infection and malignancy, and how these can be harnessed to treat disease. T cells are at the center of immunotherapy. We consider the complexity of T cell functional subsets, differentiation states, and extrinsic and intrinsic influences in the design, success, and lessons from immunotherapies. The integral role of checkpoints in the immune response is highlighted by the rapid advances in FDA approvals and the use of therapeutics that target the CTLA-4 and PD-1/PD-L1 pathways. We discuss the distinct and overlapping mechanisms of CTLA-4 and PD-1 and how these can be translated to combination immunotherapy treatments. Finally, we discuss how the successes and challenges in cancer immunotherapies, such as the collateral damage of immune-related adverse events following checkpoint inhibition, are informing treatment of autoimmunity, infection, and malignancy.

Immune Checkpoint Axes Are Dysregulated in Patients With Alcoholic Hepatitis

“…Blockade of the immunosuppressive CTLA‐4, PD‐1, and PD‐L1 pathways with ICP inhibitors has been successfully used to restore and enhance the antitumor activity of cytotoxic T lymphocytes . Targeting the main inhibitory ICPs (CTLA‐4, lymphocyte‐activation gene 3 [LAG‐3], PD‐1, and T‐cell immunoglobulin and mucin domain 3 [TIM‐3]) pathways has also been explored for therapeutic intervention in inflammatory diseases . Recently, ex vivo blockage of PD‐1 and TIM‐3 has been shown to restore functions of immune cells from patients with AH …”

“…(9,10) Targeting the main inhibitory ICPs (CTLA-4, lymphocyte-activation gene 3 [LAG-3], PD-1, and T-cell immunoglobulin and mucin domain 3 [TIM-3]) pathways has also been explored for therapeutic intervention in inflammatory diseases. (11,12) Recently, ex vivo blockage of PD-1 and TIM-3 has been shown to restore functions of immune cells from patients with AH. (6) ICP molecules also exist in soluble forms.…”

3D Immunocompetent Organ‐on‐a‐Chip Models

“…[ 42 ] These in vitro immune OOC models can also provide the platforms for the development of immunotherapies against infections, cancers, and autoimmunity, among others. [ 43 ] However, the structural complexity of the immune tissues as well as spatiotemporally dynamic cell–cell and cell–ECM interactions complicate and thus limit their successful engineering in vitro. [ 44 ]…”

PD-1 receptor on immune cells, its expression and potential role in cancer therapy

“…Hence, special attention is drawn to these costimulatory and coinhibitory interactions, since appropriate pathways are involved in immune escape of malignant tissues or virus-infected cells, as well as in development of autoimmune reactions [4]. The costimulatory and inhibitory receptors are not limited to naïve T cells, being also active in regulatory, effector and memory T cells.…”

“…И. П. Павлова, Санкт-Петербург, Россия 2 Отдел иммунологии, Институт экспериментальной медицины, Санкт-Петербург, Россия 3 Отдел онкоиммунологии, Национальный медицинский научно-исследовательский центр онкологии им. Н. Н. Петрова, Санкт-Петербург, Россия4 Отдел фундаментальной медицины, Дальневосточный федеральный университет, Владивосток, Россия…”