Cancer immunotherapies: advances and bottlenecks

Abstract

Immunotherapy has ushered in a new era in cancer treatment, and cancer immunotherapy continues to be rejuvenated. The clinical goal of cancer immunotherapy is to prime host immune system to provide passive or active immunity against malignant tumors. Tumor infiltrating leukocytes (TILs) play an immunomodulatory role in tumor microenvironment (TME) which is closely related to immune escape of tumor cells, thus influence tumor progress. Several cancer immunotherapies, include immune checkpoint inhibitors (ICIs), cancer vaccine, adoptive cell transfer (ACT), have shown great efficacy and promise. In this review, we will summarize the recent research advances in tumor immunotherapy, including the molecular mechanisms and clinical effects as well as limitations of immunotherapy.

Keywords: cancer immunotherapy; immune checkpoint blockade; neoadjuvant immunotherapy; tumor microenvironment.

Figure 1

Structure and biological activities of CTLA-4. As homolog of CD28, CTLA-4 possesses the same structure and shares the same ligands B7, CD80 (B7-1) and CD86 (B7-2). CTLA-4 is a divalent dimer, which contains two binding sites, whereas CD28 is a monovalent (which contains a single binding site) dimer. Although both belong to the B7 family, CD80 is a divalent dimer and CD86 is a monomer. CTLA-4 is predominantly present in the intracellular vesicles of T cells, which is due to the constitutive clathrin-dependent endocytosis of CTLA-4 from the plasma membrane, resulting in 90% of CTLA-4 being intracellular. Endocytosis of CTLA-4 is related to the dephosphorylation of its YVKM motif, once CTLA-4 is dephosphorylation, clathrin adapter AP-2 binds to GVYVKM motif of CTLA-4, rapidly inducing internalization. In the TGN, newly synthesized CTLA-4 binds to the transmembrane adapter TRIM, which promotes the formation of CTLA-4-containing vesicles and their transport to the cell surface. CTLA-4, Cytotoxic T-lymphocyte antigen 4; APC, antigen-presentation cell; TGN, trans-Golgi network; TRIM, TCR-interacting molecule; AP-2, μ2 subunit of the clathrin adaptor protein complex.

Figure 2

Interactions between antigen presenting cell and T cell. The major histocompatibility complex-peptide (pMHC) complex on APC or tumor cell recognizes and binds TCRs from T cells, while CD80/CD86 binds CD28 and fully activates TCR-CD28 signaling, promoting T cell activation, proliferation, and triggering the expression of associated transcription factors such as nuclear factor of activated T cells (NF-AT), activator protein 1 (AP-1) and nuclear factor-κB (NF-κB). PD1 could bind with PD-L1 expressed by APC or tumor cell and cause dephosphorylation of Zap70 and Ras by recruiting phosphatases, such as SHP2, to the tyrosine-based immunoreceptor switch motif (ITSM) in the intercellular domain of PD1, inducing inhibition of the relevant pathway. Besides, PD1 increases the expression of transcription factors such as BATF (basic leucine zipper transcription factor, ATF-like) to inhibit T cell function. LAG-3 contains four IgSF domains, each of which contains a glycosylation site. There’re several ligands of LAG-3 like LSECtin expressed on the surface of APC or tumor cells, and FGL-1 secreted by tumor cells. FGL-1 binds to D1 and D2 domain of LAG-3 and LSECtin binds to D2 domain of LAG-3. TIGIT is composed of an extracellular Ig variable (IgV) domain, a type 1 transmembrane domain, and a cytoplasmic tail with two inhibitory motifs: an immunoreceptor tyrosine-based inhibitory motif (ITIM) and an Ig tail-tyrosine (ITT)-like motif. Binding to its ligand phosphorylates the cytoplasmic tail of TIGIT which binds to cytosolic adaptor growth factor receptor-bound protein 2 (Grb2), recruiting SH2-containing inositol phosphate-1 (SHIP-1) which inhibits PI3K and MAPK signaling cascades.

Figure 3

Different cancer vaccine administration routes. DNA or RNA or peptides of screened tumor-associated antigens are injected into dendritic cells in tumor-draining lymph nodes by various routes (intravenous, intramuscular or subcutaneous). DNA or RNA vaccines can be delivered directly intratumorally, e.g., DNA vaccines can be electroporated directly at the injection site, and RNA vaccines can be delivered intravenously via nanoparticles (e.g., liposomes), which contribute to the delivery of the vaccine to lymph node-resident dendritic cells (DCs). In addition, DNA and RNA vaccines can also be delivered in vitro by presenting to patient-derived PBMC-isolated DC cells, which are then administered subcutaneously, intramuscularly, intranodally, or intravenously into the patient. IM, intramuscular; pMHC-I, peptide-MHC class I complexes; PBMC, Peripheral blood mononuclear cell.

Figure 4

Selective replication of oncolytic virus (OVs) in tumor cells. OVs can specifically infect tumor cells and replicate in tumor cells until the tumor cells lyse and release nascent virus to infect neighboring tumor cells. In normal cells, OVs replicate at low or no levels due to antiviral signaling and other mechanisms. Following infection with OV, tumor cells release antiviral cytokines to initiate an antiviral response.