Another Immune Checkpoint Emerges as Anticancer Target

Jane de Lartigue, PhD
Published Online: Tuesday, September 24, 2013

Figure. One View of IDO’s Impact on Immunity

One View of IDO’s Impact on Immunity

CTLA-4 indicates cytotoxic T lymphocyte-associated antigen 4; DC, dendritic cell; IDO, indoleamine‑2, 3‑dioxygenase; IL, interleukin; NK, natural killer.
In addition to being expressed on tumor cells, IDO is also expressed on DCs in the tumor-draining lymph nodes. IDO-activated DCs set off a cascade of events that can impair immune responses.

Douglas Hanahan and Robert Weinberg acknowledged the importance of the immune system in cancer development in 2011, when they added immune evasion to their list of “hallmark” abilities that are essential for the transformation of normal cells into cancerous ones. Researchers have begun to uncover some of the complex mechanisms employed by cancer cells that enable them to fly under the radar of the host’ s immune system, and a new class of immunotherapeutic anticancer agents has emerged as a result.

Among them are agents that target immune checkpoints—inhibitory signaling pathways that switch off the T cells of the immune system. Indoleamine (2,3)-dioxygenase (IDO) was recently identified as a checkpoint protein involved in generating the immunosuppressive tumor microenvironment that supports tumor growth. IDO inhibitors have been developed that have shown promising antitumor activity in early clinical trials, and appear to be synergistic in combination with chemotherapy and other forms of immunotherapy.

What Is IDO?

IDO is an enzyme with two isoforms (IDO1 and IDO2) that acts at the first step in the metabolic pathway that breaks down the essential amino acid tryptophan. In the late 1990s, it was discovered that IDO played a role in modulation of the immune response when researchers demonstrated that IDO expression prevented T cell-driven immune rejection of a genetically distinct fetus in pregnant female mice.

IDO exerts its immunomodulatory effects by shutting down the effector T cells of the immune system. There are several, not necessarily mutually exclusive theories as to how exactly it does this. The tryptophan starvation theory posits that the local depletion of tryptophan by IDO leads to cell cycle arrest and death of T cells (which are sensitive to decreases in tryptophan levels), while the tryptophan metabolite theory suggests that certain downstream metabolites of tryptophan are toxic to T cells. IDO expression also directly activates the regulatory T cells (a subset of T cells whose major function is to shut down T cell-mediated immunity at the end of an immune reaction).

Since the overall outcome of IDO function is an inhibition of the immune response, it joins the proteins cytotoxic T lymphocyte antigen-4 (CTLA-4) and programmed death 1 (PD-1) in the group known as immune checkpoint proteins. These proteins help to keep the immune system in check and bring an immune reaction to an end at the appropriate time.

How IDO Contributes to Immune Evasion

There has been substantial interest in the checkpoint proteins in recent years (Table). The ability to evade the immune system has been added to the list of hallmark capabilities acquired by normal cells that drives their transformation into a malignant state. One of the ways in which cancer cells are able to evade the immune system is by hijacking the checkpoint proteins; overexpression of these proteins on tumor cells enables a tumor to dampen down the immune response against it.

Table. Checkpoint-Targeting Agents in Development

Checkpoint Protein Description Agent/Industry Sponsor(s) Stage of Development
Cytotoxic T-lymphocyte antigen 4 (CTLA-4) The first immune-checkpoint receptor to be clinically targeted, CTLA-4 is a receptor expressed exclusively on T cells, where it regulates the early stages of T-cell activation. It acts as an “off switch” counteracting the activity of the T cell co-stimulatory receptor CD28 and dampening T- cell activation. Ipilimumab (Yervoy) Bristol-Myers Squibb FDA-approved for melanoma; phase I, II, and III trials ongoing for a wide variety of different cancers, including prostate cancer, pancreatic cancer, and B-cell lymphoma (NCT01057810, NCT01729806, NCT01473940, NCT01896869)
  Tremelimumab (formerly ticilimumab) MedImmune LLC Phase III trials in advanced melanoma discontinued; ongoing phase I and II trials in hepatocellular carcinoma, melanoma, and mesothelioma (NCT01853618, NCT01103635, NCT01843374, NCT01655888)
Programmed death-1
(PD-1)
PD-1 is expressed on the surface of activated T cells. As with CTLA-4, it acts as an inhibitory receptor. Binding to its ligands (PD-L1 and PD-L2), which are expressed on the surface of antigen-presenting cells, leads to dampening of T-cell activation. Pidilizumab (CT-011) CureTech Ltd Phase II trials in a variety of hematologic malignancies and solid tumors, including pancreatic cancer, prostate cancer, metastatic melanoma, and follicular lymphoma (NCT01435369, NCT00904722, NCT01313416, NCT01420965)
  Nivolumab (BMS-936558) Bristol-Myers Squibb) Phase III trials in advanced melanoma, metastatic renal cell carcinoma, and metastatic NSCLC; phase I and II trials in a variety of cancers (NCT01844505, NCT01668784, NCT01673867)
  Lambrolizumab (MK-3475) Merck Phase II/III trial in NSCLC; phase I trial in progressive, locally advanced, or metastatic melanoma or NSCLC (NCT01905657, NCT01295827)
PD-L1 One of the 2 ligands that activates the PD-1 pathway. BMS-936559 Bristol-Myers Squibb Phase I trial in multiple cancers (NCT00729664)
  MPDL3280A Genentech Phase I and II trials in metastatic melanoma, NSCLC, and locally advanced or metastatic hematologic malignancies and solid tumors (NCT01656642, NCT01846416, NCT01375842)
PD-L2 Same as above. AMP-224 Amplimmune/GlaxoSmithKline Phase I trials in advanced cancer (NCT01352884)
Lymphocyte activation gene 3 (LAG3) Receptor that inhibits T-cell activation. IMP321 (ImmuFact) Immutep Ongoing phase I/II in melanoma; completed phase I trials in breast cancer and renal cell carcinoma (NCT01308294, NCT00349934, NCT00351949)
B7 homolog 3 (B7-H3) Another member of the B7 superfamily that includes CTLA-4 and PD-1. B7-H3 is a ligand that inhibits T-cell activation. MGA271 MacroGenics Phase I trial in multiple refractory cancers (NCT01391143)
Indoleamine (2,3)-dioxygenase (IDO)
(PD-1)
A metabolic enzyme expressed by both tumor and tumor-infiltrating cells. IDO modulates T-cell behavior by depleting amino acids that are essential for their function. Indoximod NewLink Genetics Corporation Phase II trials of metastatic breast cancer and refractory metastatic prostate cancer in combination with sipuleucel-T (NCT01792050, NCT01560923)
  INCB024360 Incyte Corporation Phase II trial of biochemical-recurrent ovarian cancer and a phase I/II trial in unresectable or metastatic melanoma (NCT01685255, NCT01604889)

NSCLC indicates non-small cell lung cancer. For more information on clinical trials, visit www.ClinicalTrials.gov.

IDO overexpression has been observed in a wealth of tumor types, including prostate, colorectal, pancreatic, and cervical tumors, and is correlated with poorer survival in many cases. Increased IDO protein levels drive growth arrest and apoptosis of the effector T cells, a group of immune cells that includes cytotoxic T cells,helper T cells, and natural killer (NK) cells that mediate the immune system’s ability to destroy pathogens. By reducing the number of effector T cells, IDO overexpression prevents the immune system from effectively destroying cancer cells.

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