TIGIT Induces (CD3+) T Cell Dysfunction in Colorectal Cancer by Inhibiting Glucose Metabolism

This article provides an update on the global cancer burden using the GLOBOCAN 2020 estimates of cancer incidence and mortality produced by the International Agency for Research on Cancer. Worldwide, an estimated 19.3 million new cancer cases (18.1 million excluding nonmelanoma skin cancer) and almost 10.0 million cancer deaths (9.9 million excluding nonmelanoma skin cancer) occurred in 2020. Female breast cancer has surpassed lung cancer as the most commonly diagnosed cancer, with an estimated 2.3 million new cases (11.7%), followed by lung (11.4%), colorectal (10.0 %), prostate (7.3%), and stomach (5.6%) cancers. Lung cancer remained the leading cause of cancer death, with an estimated 1.8 million deaths (18%), followed by colorectal (9.4%), liver (8.3%), stomach (7.7%), and female breast (6.9%) cancers. Overall incidence was from 2-fold to 3-fold higher in transitioned versus transitioning countries for both sexes, whereas mortality varied <2-fold for men and little for women. Death rates for female breast and cervical cancers, however, were considerably higher in transitioning versus transitioned countries (15.0 vs 12.8 per 100,000 and 12.4 vs 5.2 per 100,000, respectively). The global cancer burden is expected to be 28.4 million cases in 2040, a 47% rise from 2020, with a larger increase in transitioning (64% to 95%) versus transitioned (32% to 56%) countries due to demographic changes, although this may be further exacerbated by increasing risk factors associated with globalization and a growing economy. Efforts to build a sustainable infrastructure for the dissemination of cancer prevention measures and provision of cancer care in transitioning countries is critical for global cancer control.

The tumor microenvironment significantly influences therapeutic response and clinical outcome. Microenvironment-mediated drug resistance can be induced by soluble factors secreted by tumor or stromal cells. The adhesion of tumor cells to stromal fibroblasts or to components of the extracellular matrix can also blunt therapeutic response. Microenvironment-targeted therapy strategies include inhibition of the extracellular ligand-receptor interactions and downstream pathways. Immune cells can both improve and obstruct therapeutic efficacy and may vary in their activation status within the tumor microenvironment; thus, re-programme of the immune response would be substantially more beneficial. The development of rational drug combinations that can simultaneously target tumor cells and the microenvironment may represent a solution to overcome therapeutic resistance.

Co-inhibitory receptors, such as CTLA-4 and PD-1, have an important role in regulating T cell responses and have proven to be effective targets in the setting of chronic diseases where constitutive co-inhibitory receptor expression on T cells dampens effector T cell responses. Unfortunately, many patients still fail to respond to therapies that target CTLA-4 and PD-1. The next wave of co-inhibitory receptor targets that are being explored in clinical trials include Lag-3, Tim-3, and TIGIT. These receptors, although they belong to the same class of receptors as PD-1 and CTLA-4, exhibit unique functions, especially at tissue sites where they regulate distinct aspects of immunity. Increased understanding of the specialized functions of these receptors will inform the rational application of therapies that target these receptors to the clinic.