The yin and yang of co-inhibitory receptors: toward anti-tumor immunity without autoimmunity

Abstract

Co-inhibitory receptors are important regulators of T-cell function that define the balance between tolerance and autoimmunity. The immune regulatory function of co-inhibitory receptors, including CTLA-4, PD-1, TIM-3, TIGIT, and LAG-3, was first discovered in the setting of autoimmune disease models, in which their blockade or deficiency resulted in induction or exacerbation of the disease. Later on, co-inhibitory receptors on lymphocytes have also been found to influence outcomes in tumor and chronic viral infection settings. These receptors suppress T-cell function in the tumor microenvironment (TME), thereby making the T cells dysfunctional. Based on this observation, blockade of co-inhibitory receptors (also known as checkpoint molecules) has emerged as a successful treatment option for a number of human cancers. However, severe autoimmune-like side effects limit the use of therapeutics that block individual or combinations of co-inhibitory receptors for cancer treatment. In this review we provide an overview of the role of co-inhibitory receptors in autoimmunity and anti-tumor immunity. We then discuss current approaches and future directions to leverage our knowledge of co-inhibitory receptors to target them in tumor immunity without inducing autoimmunity.

Fig. 1

The Yin and Yang of co-inhibitory receptors. Schematic representation of the co-inhibitory receptors’ functional role in autoimmunity and cancer. In the tumor, co-inhibitory receptors on T cells dampen T-cell effector functions thereby enhancing tumor progression and correlating with worse clinical outcome. In autoimmunity, these receptors play a role in reducing local and systemic tissue inflammation, maintaining tissue tolerance, and their increased expression is associated with a good clinical outcome

Fig. 2

Novel approaches for checkpoint blockade therapy to avoid autoimmune-like disease. Top: Current immune checkpoint blockade inhibits the signaling of co-inhibitory receptors thereby enhancing T-cell effector functions. At the tumor site, these hyper-functional T cells mediate strong anti-tumor immunity thereby reducing tumor growth (left). However, the T cells with specificity for self-antigens induce severe autoimmune-like irAEs by becoming hyper-functional and inducing tissue inflammation (right). IrAEs are mostly found in tissues with high microbial exposure, such as the skin, intestine, and liver. At homeostasis these tissues manifest a well-regulated tolerogenic environment, that is disrupted with checkpoint blockade. Bottom: Novel approaches should target new receptors mediating a potent immune response in the tumor (left) while reframing from inappropriate immune responses in the periphery against self-antigens (right). Potential mechanisms are: (1) in the periphery and in normal tissues the receptors act differentially, (2) the receptors are not expressed in the periphery, (3) the blockade only occurs in the tumor and not in the peripheral tissues

Fig. 3

Therapeutic targeting of co-inhibitory receptors in autoimmunity and cancer. Timeline of discovery and therapeutic targeting of the five co-inhibitory receptors discussed in this review: CTLA-4, LAG-3, PD-1, TIM-3, TIGIT. The clinical or preclinical investigations and FDA-approved drugs are listed for both autoimmunity (red) and cancer (blue) according to https://clinicaltrials.gov and https://www.fda.gov

Fig. 4

Shared transcriptional signature of inflammatory Th1 and Th17 cells and exhausted T cells. Pathogenic Th17 cells are established drivers of multiple autoimmune diseases. Exhausted T cells are hypo-functional T cells preventing active tumor immunity. Both T-cell states share part of their transcriptional signature. Interestingly, when projecting the cancer exhaustion signature and the pathogenic Th17 signature on the tSNE plot of single-cell CD8⁺ TILs (top), multiple single cells show enrichment for both signatures, suggesting that shared modules or transcriptional programs are activated in those cells. Members of this shared signature could play a key role in T-cell activation and later exhaustion. Targeting of these genes could potentially yield in an enhanced anti-tumor immunity without increased autoimmunity