Cancer Evasion of Immune Surveillance

Article 5

Immune Tolerance

Tolerance to tumors likely operates predominantly at the level of T cells. T cells hold the capacity to kill growing tumors, either directly through cytotoxic T lymphocyte activity, or indirectly through multiple CD4+-dependent mechanisms. It is therefore likely that the induction of antigen-specific tolerance among T cells is of utmost importance for tumor survival.

Tumors use mechanisms of tolerance induction to turn off T cells specific for tumor-associated antigens. Two mechanisms that result in immune tolerance of tumors involve regulatory T cells and dendritic cells:

  • Regulatory T cells have emerged as a central player in maintenance of the tolerant state as well as general downregulation of immune responses to pathogens.
  • Steady presentation of self antigens by immature dendritic cells to T cells trains the immune system not to attack cells and tissues in the body. Tumors may co-opt this process, called anergy.

Altering the Tumor Microenvironment

Some oncogenic pathways in tumors result in the production of factors that alter the tumor microenvironment in ways that are hostile to antitumor immune responses. These oncogenic pathways may not only protect the tumor from antitumor immune responses but may also shift immune responses to those that support and promote tumor growth.

Two key mechanisms involved in altering the tumor microenvironment include:

  • Production of molecules that inhibit immune responses
  • Activation of immune checkpoints

Let's look at the activation of immune checkpoints in more detail, as this relates to our understanding of the atezolizumab MOA.

Activation of naïve T cells by antigen-presenting cells requires a second co-stimulatory signal in addition to the signal conferred by MHC presentation of antigen. Together, these 2 signals allow T cells to proliferate, acquire antitumor cytotoxic functions, and migrate to disease sites for tumor-cell killing. T-cell activation is regulated by a number of inhibitory signals. This helps avoid prolonged immune responses that may damage normal tissues. Together, these stimulatory and inhibitory signals that are intrinsic to T cells are known as immune checkpoints, and it is the balance between these signals that results in properly modulating immune responses, as shown.

Multiple co-stimulatory (denoted by +) and co-inhibitory (denoted by –) ligand-receptor interactions ultimately determine the amplitude of T-cell activation and the potency of cytotoxic
T-cell responses in tissue and tumor.

However, the function of immune checkpoints can be dysregulated by tumors as they mute immune responses that "threaten" them.

There are many immune checkpoint pathways, two of which have been extensively studied and are of particular importance: the CTLA-4 checkpoint and the PD-1/PD-L1 checkpoint.

Cancer evasion of immune surveillance is
comprised of immune tolerance and alteration of the tumor microenvironment. Select each tile on the left to learn more.