Targeting inhibitory pathways in cancer immunotherapy

Abstract

The clinical success of adaptive transfer of in vitro expanded antigen-specific CD8(+) T cells isolated from patients' tumors has demonstrated that effector cells of the adaptive immune system can effectively eliminate even large tumor masses. Nevertheless, cancer vaccines that aim to expand such CD8(+) T cells in situ have had remarkably little success in spite of numerous attempts. Recent advances in basic immunology have revealed layers of complexity controlling activation and maintenance of adaptive immune responses that are tightly controlled by immunoinhibitory pathways to avoid horror autotoxicus. During tumor progression the activities of negative pathways increase and together with cancer immune evasion tactics presumably prevent induction of an efficacious immune response by cancer vaccines that solely provide more antigen to an already suppressed system. Cancer vaccines may thus need to readjust the imbalance of the cancer patients' immune system by inhibiting immunoinhibitors; such regimens have shown preclinical efficacy and are now entering clinical trials hopefully ending the Kafkaesque futility of cancer vaccines.

Figure 1

T cell activation requires two signals; signal one is delivered through the T-cell receptor (TCR) by its engagement with a peptide–major histocompatibility complex (MHC), and signal two is delivered by engagement of either B7 family members or other co-stimulatory/co-inhibitory molecules, which are involved in fine-tuning T cell responses [31]. The binding of CD80 (B7.1) and CD86 (B7.2) to CD28 or CTLA-4 can lead to co-stimulation or co-inhibition signaling, respectively. Engagement of inducible costimulatory (ICOS) molecule and its ligand ICOSL can provide both negative and positive signals. The PD-1:PD-L1/PD-L2 pathway has inhibition effects on T cells. PD-L2 has also been shown to mediate co-stimulatory signals; however, its receptor has not been identified [31]. Lymphocyte-activation gene 3 (LAG-3) has been associated with inhibitory signaling through interactions with the TCR–CD3 complex [62]. HVEM can send positive or negative signals upon interaction with LIGHT and LTα or BTLA and CD160, respectively [63]. Recent studies have shown B7-H3 as a co-stimulator and co-inhibitor of T cell responses, while B7-H4 is a negative regulator of T cell responses. The receptors for B7-H3 and H7-H4 have not yet been identified [31]. Secondary signaling provided by B7 family members are also involved in the network of interactions between the tumor–stroma tissue and T cells. Human tumor cells have been reported to express co-inhibitory molecules, such as ICOSL, B7-H3, B7-H4, PD-L1 and PD-L2 [18,64,65]. Tregs also express co-inhibitory molecules, such as LAG-3, CTLA-4, ICOS, HVEM and PD-L1 [18]. *Blockage of these molecules has been shown to enhance in vivo anti-tumor immunity [36,42,62,64,65].