Immune checkpoint therapy for solid tumours: clinical dilemmas and future trends

Abstract

Immune-checkpoint inhibitors (ICBs), in addition to targeting CTLA-4, PD-1, and PD-L1, novel targeting LAG-3 drugs have also been approved in clinical application. With the widespread use of the drug, we must deeply analyze the dilemma of the agents and seek a breakthrough in the treatment prospect. Over the past decades, these agents have demonstrated dramatic efficacy, especially in patients with melanoma and non-small cell lung cancer (NSCLC). Nonetheless, in the field of a broad concept of solid tumours, non-specific indications, inseparable immune response and side effects, unconfirmed progressive disease, and complex regulatory networks of immune resistance are four barriers that limit its widespread application. Fortunately, the successful clinical trials of novel ICB agents and combination therapies, the advent of the era of oncolytic virus gene editing, and the breakthrough of the technical barriers of mRNA vaccines and nano-delivery systems have made remarkable breakthroughs currently. In this review, we enumerate the mechanisms of each immune checkpoint targets, associations between ICB with tumour mutation burden, key immune regulatory or resistance signalling pathways, the specific clinical evidence of the efficacy of classical targets and new targets among different tumour types and put forward dialectical thoughts on drug safety. Finally, we discuss the importance of accurate triage of ICB based on recent advances in predictive biomarkers and diagnostic testing techniques.

Fig. 1

Interaction of novel immune checkpoint receptors and their respective ligands. Cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) competitively binds to CD80/86 and limits initial T cell activation; programmed cell death protein-1 (PD-1) binds to PD-L1 and inhibits effector T activation and expansion; lymphocyte activation gene-3 (LAG-3) competitively binds to major histocompatibility complex II (MHC II) and inhibits effector T cell activation; T cell immunoglobulin and mucin domain 3 (TIM-3) binds to carcinoembryonic antigen cell adhesion molecule 1 (CEACAM-1) or Galectin-9 and triggers CD8⁺ T cell exhaustion; B and T Lymphocyte Attenuator (BTLA) binds to Herpesvirus entry mediator (HVEM) and suppresses TCR signalling; T cell Immunoglobulin and ITIM domain (TIGIT) binds to CD122 or CD155 and downregulates cell functions of T cells and NK cells;, Co-stimulatory receptors include inducible costimulatory molecule (ICOS), glucocorticoid-induced TNF receptor family-related protein (GITR), TNF receptor superfamily member 4 (OX40), and TNF receptor superfamily member 9 (4-1BB). Tryptophan (Trp) catabolism molecules (IL4I1 and IDO-1) and adenosine signalling molecules (CD39 and CD73) are also involved

Fig. 2

Important genes signalling pathways and metabolic alterations associated with ICB responsiveness or resistance in tumour cells. Anti-tumour immunity is mainly through the killing effect of CTL on tumour cells. Tumour gene mutations involved in the PI3K-Akt-mTOR axis, hypoxia-inducible factor-1α (HIF-1α) pathway, Janus kinase (JAK)/signal transducer and activator of transcription (STAT) pathway, and NF-κB pathways will affect PD-1 blockade responsiveness and resistance. Metabolic alterations of glycolysis, aggressive depletion of amino acids, and immune-suppressive productions are essential factors influencing CTL anergy and ICB resistance

Fig. 3

Transcriptional regulation of dendritic cells (DCs) and exhausted T cells (T_EX). a Cell phagocytosis is triggered and results in phagosomal degradation in the cytoplasm of DC cells. Cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) signalling is activated and releasing type I interferons (IFNs), mainly comprised of IFN-α and IFN-β. Antigens processed are loaded onto MHCs, which subsequently promote the activation of Th1 cells and CTL cells. IFN-γ released by these activated T cells will stimulate the non-canonical NF-κB pathway and release IL-12. Mature immunoregulatory DCs (mDCreg) produces IL-4 and inhibits the functions of cDCs and Th1 cells. b Transcriptional regulation of T_EX cells. T cell receptor (TCR) responsive network of transcription factors, including the nuclear factor of activated T cells, cytoplasmic component 1 (NFATC1), thymocyte selection-associated high mobility group box protein (TOX), and B lymphocyte-induced maturation protein 1 (BLIMP1) are overexpressed in T_EX cells. NFATC1 and TOX promote the expression of PD-1 (encoded by Pdcd1) and LAG-3 (encoded by Lag3). Highly expressed BLIMP1 induces granzyme B (Gzmb) expression and represses TCF1 expression. Furthermore, TOX induces eomesodermin homologue (EOMES) and nuclear receptor subfamily 4 group A (NR4A) expressions. All of them can inhibit T-bet, which results in the decrease of IFN-γ releasing. IRF4 interferon regulatory factor 4; BATF basic leucine zipper transcriptional factor ATF-like

Fig. 4

Novel immunotherapy-enhancing combination regimens. a The four routes of administration currently used in clinical practice are oral medication, intravenous injection, subcutaneous injection and intratumoral injection respectively. b Gut microbiome and mRNA vaccine therapy rely on dendritic cell (DC)-mediated presentation of tumour-associated peptides, antigens, or epitopes derived from tumour lysates to T cells of the adaptive immune system through MHC class II-T cell receptor (TCR) interaction. The cytotoxic T lymphocytes (CTLs) that are subsequently activated interrogate and destroy tumour cells containing tumour-associated antigens presented on MHC class I molecules. Nanomedicine therapy is mainly used to deliver drugs to target organs. Oncolytic virus therapy can directly infect tumour cells to cause lysis and death, or it can translate target proteins in the form of gene editing and play a corresponding tumour-killing role