Contributed by Kimberly Holloway, Ph.D.
Immune-checkpoint inhibitors is a popular topic of current discussion within the realm of tumor therapeutics. Most notably cytotoxic T lymphocyte antigen 4 (CTLA-4) and programmed death receptor 1 (PD-1) have garnered the most attention. The first immune checkpoint inhibitor associated with overall survival within a phase 3 metastatic melanoma study, Ipilimumab, is a fully humanized antibody against cytotoxic T-lymphocyte–associate-d antigen 4 (CTLA-4) antibody. 1,2 Blockade of PD-1 has achieved revolutionary clinical impact in many solid cancers; however, there has been certain roadblocks which have prevented full response to anti-PD-1 therapy.3–5 A significant percentage of cancer patients fail to respond to these therapies due to compensatory immune inhibitory pathways. 6
TIM-3 is now
In 2016, Koyama and colleagues compared the immune cells present in effusion samples collected from patients whom developed resistance to anti-PD-1 therapy with that of immune cells from five patients with non-small-cell lung cancer who had not received anti-PD-1 treatment.7 Higher levels of TIM-3 were detected in T cells from the PD-1 resistant patients compared with the other patients.7 T-cell immunoglobin mucin-3, TIM-3, is highly expressed on tumor infiltrating dendritic cells and actively competes with nucleic acids released from dying tumor which effectively inhibits stimulation of the innate immune response by nucleic acids. 6, 8 This weakening of innate immunity by TIM-3 exposes a major vulnerability in which tumor cells are now able to bypass pro-inflammatory cytokines. In addition, Tim-3 inhibits immune responses and promotes tolerance by regulating multiple targets including CD4+ T, CD8+ T, T-regulatory (Tregs), Forkhead Box P3 (FoxP3), Type 1 regulatory T (Tr1), Natural killer (NK), dendritic (DCs), and myeloid-derived suppressor (MDSCs) cells.9 Such findings suggest the therapeutic targeting of TIM-3 within the context of cancer. However, due to its extensive role in immune response, TIM-3 mAbs can also influence other pathophysiological mechanisms such as the severity of experimental autoimmune encephalomyelitis (EAE).10 In addition, administration of TIM-3 mAbs has found to not inhibit tumor growth on its own.11 Therefore, careful thought on how and when to use TIM-3 mAbs should be considered.
In 2010, it was shown that combination of TIM-3 and PD-1 mAbs had a much greater antitumor effect than administration of TIM-3 or PD-1 mAbs alone.11 Therefore, a two-tier therapeutic model in which CTLA-4 and PD-1 represent the ﬁrst tier of co-inhibitory receptors that are primarily responsible for maintaining self-tolerance and the second tier which includes TIM-3 as a co-inhibitory molecules that regulates immune responses at sites of tissue inﬂammation has been introduced as an alternative resolution to resistance.9 As expected, the effect of PD-1 blockade is proportionally larger than that of Tim-3 blockade alone. However, Tim-3 blockades preferentially affect tumor tissue Treg and IL-10-producing Tr1 cells while additionally affecting dendritic cell phenotype and dampening MDSCs. Thus, there has been a consensus that different checkpoint receptor blockades can be combined to achieve distinct effects on the immune response.9
Detection of Human TIM3 in FFPE tonsil by IHC. Antibody: Rabbit anti-TIM3 recombinant monoclonal [BLR033F] (A700-033). Secondary: HRP-conjugated goat anti-rabbit IgG (A120-501P). Substrate: DAB.
Detection of human TIM3 In FFPE RPMI-8226 cells by ICC. Antibody: Rabbit anti-TIM3 recombinant monoclonal [BLR033F] (A700-033) Secondary: HRP-conjugated goat anti-rabbit IgG (A120-501P). Substrate: DAB.