Recent Advances in Molecular Mechanisms of Cancer Immunotherapy

Abstract

Cancer is among the current leading causes of death worldwide, despite the novel advances that have been made toward its treatment, it is still considered a major public health concern. Considering both the serious impact of cancer on public health and the significant side effects and complications of conventional therapeutic options, the current strategies towards targeted cancer therapy must be enhanced to avoid undesired toxicity. Cancer immunotherapy has become preferable among researchers in recent years compared to conventional therapeutic options, such as chemotherapy, surgery, and radiotherapy. The understanding of how to control immune checkpoints, develop therapeutic cancer vaccines, genetically modify immune cells as well as enhance the activation of antitumor immune response led to the development of novel cancer treatments. In this review, we address recent advances in cancer immunotherapy molecular mechanisms. Different immunotherapeutic approaches are critically discussed, focusing on the challenges, potential risks, and prospects involving their use.

Keywords: antitumor response; cancer immunotherapy; cytokines; immune checkpoints.

Figure 1

The number of scientific publications related to cancer immunotherapy (Search done through Science Direct database on 30 March 2023).

Figure 2

The main causes of human cancers and hallmarks of cancer established by Hanahan and Weinberg. Created with BioRender.com, accessed on 23 April 2023.

Figure 3

Schematic illustration of the cancer-immunity cycle. (CTL: cytotoxic t lymphocytes; APC: an antigen-presenting cell). Adapted with permission from Chen et al. [40].

Figure 4

Cancer immunotherapy types include the use of immune-checkpoint inhibitors, cancer vaccines, cytokines, viruses, and adoptive cell transfer. Created with BioRender.com, accessed on 23 April 2023.

Figure 5

Schematic illustration of the mutual regulation by various immune checkpoints between cancer cells and T cells. The interaction between Major Histocompatibility Complex class (MHC) molecules and the T-cell receptor (TCR) is a critical step in the activation of T cells. The interaction between PD-1 (programmed cell death protein 1) on the surface of T cells and PD-L1/2 (programmed cell death ligand 1/2) expressed on tumor cells inhibits TCR signaling. A similar effect is observed when CD80/CD86 molecules present in cancer cells bind with cytotoxic T-lymphocyte-associated protein 4 (CTLA4). Inhibitory effects on TCR signaling and T-cell activity have been attributed to the interaction between TIM-3 (T-cell immunoglobulin and mucin-domain containing-3) and its ligand Galectin-9 (Gal-9). In turn, T-cell immunoreceptor with Ig and ITIM domains (TIGIT) and CD96 can suppress T-cell activation by binding to CD155 with a higher affinity than CD226, which in turn outcompetes CD226 for the binding site. The binding of TIGIT with CD155 induces an inhibitory signal within tumor cells. This signal up-regulates IL-10 while simultaneously down-regulating IL-12. TIGIT hinders CD226 and CD155 from engaging in interaction by disrupting the homodimerization of CD226. It is currently unknown whether or not TIGIT can directly provide co-inhibitory signals in T cells once it has bound to CD155. CD226 is responsible for delivering co-stimulatory signals by binding to CD112 and CD155. CD96 is responsible for delivering co-inhibitory signals when it binds to CD111 and CD155. Created with BioRender.com, accessed on 23 April 2023. Based on [76].

Figure 6

Vascular endothelial growth factor receptor-1 (VEGFR-1)-mediated approach for improving antitumor immune response. (A) Schematic illustration of the principal; (B) antitumor activity of the anti-VEGFR-1 monoclonal antibody (mAb D16F7) in combination with anti-CTLA-4 or anti-PD-1 mAbs. Adapted with permission from Lacal et al. [110].

Figure 7

Schematic representation of oncolytic viro-immunotherapy strategies: (A) modification of endogenous genes of the virus for stimulating interferon induction, (B) virus-mediated expression of immune-stimulatory cytokines, (C) oncolytic cancer vaccine approach, and (D) synergistic effect of adaptive cell therapy and oncolytic viruses. Adapted with permission from Melzer et al. [130].

Figure 8

Cancer vaccine: (A) Following administration of cancer-specific antigens (CSAs) through vaccination (B) antigens are transported to the lymph nodes, where (C) they are uptaken by dendritic cells (DCs) and activate the B and T cells. (D) B cells produce tumor-targeted antibodies, while activated T cells and natural killer (NK) recruited to the tumor microenvironment release perforins (PFNs) and granzyme A/B (GZMA/B) and interferon γ (IFN-γ) leading to cancer cell death. Created with BioRender.com, accessed on 23 April 2023.

Figure 9

Efficient dendritic cell (DC) recruitment and activation by injectable dual-scale mesoporous silica microrod–mesoporous silica nanoparticle vaccine. Adapted with permission from Nguyen et al. [42].

Figure 10

Cytokines that are involved in immunogenic cell death induction. Damage-associated molecular patterns (DAMPs) are released from dying cells during immunogenic cell death (ICD) and facilitate tumor antigen presentation and augment adaptive immunity. Cancer cells secrete calreticulin (CRT), which binds to the CD91 receptor on dendritic cells (DCs), and high-mobility group protein 1 (HMGB1), which is a ligand for the Toll-like receptor (TLR-4) on DCs. In addition, DSc’s P2X purinoceptor 7 (P2RX7) engages with ATP that cancer cells secrete. Created with BioRender.com, accessed on 23 April 2023. Modified from Showalter et al. [176].

Figure 11

Antitumor effect of vaccinia virus expressing interleukin-2 (VV-IL-2) against malignant pleural disease. (A) The principal of the approach; (B) antitumor effect upon the administration of VV-IL-2, which reduced tumor burden and increased PD-1+ tumor-infiltrating T lymphocytes and survival. Phosphate-buffered saline (PBS) was used as a control (* p < 0.05, ** p < 0.01). Adapted from Ekeke et al. [180].

Figure 12

Schematic illustration of the CAR T-cell therapy. Created with BioRender.com, accessed on 23 April 2023.

Figure 13

Inverted cytokine receptor-modified chimeric antigen receptor T cells exhibit noticeably antitumor activity. (A) Schematic drawing of mice engrafted with cancer cells and treated with either CAR/ICR T cells or CAR. (B) CAR and CAR/ICR T cells expansion and persistence as measured by bioluminescence imaging. (C) The reduction in tumor volume for CAR/ICR T cell-based treatment. (D) Superimposition of tumor volume and T-cell signal in CAR/ICR-based treated mice. (E) Images of mice administered with two treatments: CAR, CAR/ICR T cells, or control. Adapted with permission from Mohammed et al. [192].