Mechanisms of Action of Immune Checkpoint Inhibitors

Immune Checkpoint and Immune Checkpoint Inhibitors

Immunological checkpoints, as important regulatory molecules of immunological activation, are critical to the immune system's function. Cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) and programmed cell death protein 1 (PD-1) are the two most widely recognized immune-suppressive checkpoint molecules. Many other immune checkpoints have also been identified, such as lymphocyte-activation gene 3 (LAG3), T-cell immunoglobulin and mucin domain 3 (TIM-3), T-cell co-stimulator (ICOS), and others.

Immune checkpoint inhibitors (ICIs) are a class of drugs that can block these checkpoint molecules, allowing for the restoration of anti-tumor immune responses. Some monoclonal antibodies targeting immunological checkpoints have resulted in considerable therapeutic responses.

Mechanisms of Action of ICIs in Cancer

Improved understanding of the molecular and immunologic mechanisms of ICI response may lead to the identification of novel predictive and/or prognostic biomarkers, as well as the best combination/sequencing of ICI therapy in the clinic.

• Enhanced Tumor-Specific T Cell Activity
  Checkpoint inhibitors promote the reinvigoration of exhausted or anergic tumor-specific T cells which allows T cells to recognize and attack cancer cells more effectively. A study found activation markers such as Ki67 and HLA-DR were raised on T cells in patients receiving therapy for anti-PD-L1 or anti-PD-1. Various PD-1⁺CD8⁺ T cells have been demonstrated to multiply or become activated in response to anti-PD-1/PD-L1 therapy in chronic infection and malignancy. In melanoma and renal cell carcinoma, anti-CTLA-4 treatment results in an influx of CD8⁺ T lymphocytes in the tumor microenvironment.

Fig 1 Anti-PD-1/PD-L1 and anti-CTLA-4 antibodies target immune cells.¹

• T cell metabolic reprogramming
  Nutrient competition between cells affects tumor cell growth, survival, and function. Metabolic activity is directly related to T cell fitness and function. Tumor and immune cells compete for glucose in the tumor microenvironment. PD-L1 signaling affects the Akt/mTOR pathway, resulting in decreased glycolytic enzyme translation and decreased glycolysis. Anti-CTLA-4 and anti-PD-1 blocking therapy is shown to rectify tumor-induced glucose limitation in tumor-infiltrating lymphocytes (TILs) and restore their effector activity.
• Increased Tumor Infiltration
  ICIs can cause T lymphocytes to infiltrate the tumor microenvironment. This is facilitated by the restoration of T cell function and the chemokines produced within the tumor, leading to increased immune surveillance and anti-tumor activity. TIL density is found to correlate with favorable clinical response in melanoma patients treated with anti-CTLA-4. In the serum of patients treated with both anti-PD-1 and anti-PD-L1, there is an increase in the levels of circulating IFN- and IFN-induced chemokines (CXCL-9 and CXCL-10).
• Antibody-Dependent Cell-Mediated Cytotoxicity (ADCC)
  Some ICIs additionally demonstrate ADCC activity. Through the Fc region of the antibody, they can bind to Fc receptors on immune cells like natural killer (NK) cells, macrophages, and dendritic cells, triggering their activation and subsequent killing of cancer cells.

The clinical effectiveness of ICIs has transformed cancer treatment. With many years of research experience, Creative Biolabs provides a series of professional immune checkpoint-related services based on the above mechanisms of action. In case you need additional information, please do not hesitate to contact us.

Reference

1. Granier, Clemence et al. "Mechanisms of action and rationale for the use of checkpoint inhibitors in cancer." ESMO open vol. 2,2 e000213. 3 Jul. 2017.

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