Understanding Checkpoint Inhibitors in Cancer Therapy, Mechanisms of Action, Resistance and Future Challenges

Abstract

The immune system is the human body’s natural defence against mutated cells produced as the result of DNA replicative error or by the effect of carcinogens, a process rereferred to as immune surveillance. ‘Escaping’ of cancer cells from immune surveillance leads to tumor development, metastasis and progression. Avoiding detection and destruction by the immune system are the result of cancer cells evolution, caused primarily by cancer cells’ genomic instability. On the other hand, scientists attempted for decades to exploit the anticancer effect of the immune system with limited success. However, better understanding of the mechanisms behind the cancer cells’ ability to avoid detection and suppression by the immune system resulted in the development of immune checkpoint inhibitors, a form of immunotherapy, first approved by the Food and Drug Administration (FDA) in 2011. This article reviews the pathways involved in anticancer immune response, evading and supressing of the immune system by cancer cells mechanisms of action and successes of immune checkpoint inhibitors (ICI), particularly programmed death1 (PD-1) and programmed death-ligand (PD-L1) inhibitors as well as mechanisms that result in resistance of cancer cells to ICI.

Translational Studies Using the MALT1 Inhibitor (S)-Mepazine to Induce Treg Fragility and Potentiate Immune Checkpoint Therapy in Cancer

“…[ 4 - 8 ] Tumor-associated Tregs use multiple suppressive mechanisms to constrain antitumor immune responses and impede the effectiveness of cancer immunotherapy. [ 2 , 6 , 7 , 9 - 13 ] In particular, although immune checkpoint therapy (ICT) has been transformative in treating a broad range of cancers,[ 14 - 16 ] objective response rates (ORRs) remain low for many cancer types, and initial responders may acquire resistance over time. [ 12 , 15 , 17 , 18 ] Therefore, the use of combination therapies to improve ICT ORRs is an ongoing area of research, and manipulating Tregs is one emergent option.…”

The Emerging Role of the Gut Microbiome in the Cancer Response to Immune Checkpoint Inhibitors: A Narrative Review

“…[1,2] These drugs are monoclonal antibodies that target specific proteins on cells, namely PD-1, its ligand (PDL-1), or CTLA-4, that are involved in inhibitory regulation of immune responses. [3] This in turn allows immune cells to better target tumor cells presenting non-self-antigens, thus overcoming tumor immune subversion, which is often seen in malignancies. Despite these advances, the clinical efficacy of ICIs is highly variable among cancer patients.…”