Pathophysiology of the Tumor Microenvironment in Melanoma

Adi Diab, MD:Interleukin-2 is a cytokine, and it’s basically a growth factor for a lot of immune cells, mostly T lymphocytes. This includes the subsets of the T-cell lymphocytes CD4 and CD8, as well as natural killers. Those are the cells that benefit the most from interleukin-2, and they benefit in terms of proliferation, dividing, and expanding, as well as activation. They become more of an active phenotype when they receive the signaling through the interleukin-2. Another subset of the T cells, especially in the CD4 subset, are called regulatory T cells. These are a T-cell subset that are specialized in regulating the immune system, but just like other T cells, effector T cells benefit from interleukin-2. Regulatory T cells seem to benefit the most from the regular interleukin-2 cytokine, and they expand most when they see or are exposed to these cytokines.

PD-L1 [programmed death-ligand 1] is a mechanism of tissue protection for an overactive immune system. It is kind of a negative feedback mechanism. When the infected tissue or cancer tissue gets exposed to active immune cells, the active immune cells secrete another cytokine known as interferon gamma. The exposed tissue to the interferon gamma, over time, starts upregulating a molecule called PD-L1. The goal of that PD-L1 molecule is to engage on a PD-1 [programmed cell death protein 1] molecule on the activated T cells, which are the same cells that secrete the interferon gamma. The engagement of PD-1 with PD-L1 leads to exhaustion. Then the T cells lose their ability to proliferate, secrete cytokines, and eventually kill the target. So it’s an adaptive immune protection that normal tissue has, but it’s a mechanism that’s hijacked by the cancer cells and the cancer cells become resistant to the immune system.

So when the activated T cells invade the tumor microenvironment and start secreting interferon gamma, they turn that mechanism on. Eventually the tumor tissues that do not express PD-L1, after they’re exposed to the interferon gamma from the attacking T cells, become PD-L1—positive in order to protect themselves from the attacking immune cells. But then comes the role of anti–PD-1 or anti–PD-L1 antibody-blocking agents to overcome that and keep the immune system activated.

Transcript edited for clarity.