Immunosurveillance and Immunoediting of Lung Cancer: Current Perspectives and Challenges

Abstract

The immune system plays a dual role in tumor evolution-it can identify and control nascent tumor cells in a process called immunosurveillance and can promote tumor progression through immunosuppression via various mechanisms. Thus, bilateral host-protective and tumor-promoting actions of immunity are integrated as cancer immunoediting. In this decade, immune checkpoint inhibitors, specifically programmed cell death 1 (PD-1) pathway inhibitors, have changed the treatment paradigm of advanced non-small cell lung cancer (NSCLC). These agents are approved for the treatment of patients with NSCLC and demonstrate impressive clinical activity and durable responses in some patients. However, for many NSCLC patients, the efficacy of immune checkpoint inhibitors is limited. To optimize the full utility of the immune system for eradicating cancer, a broader understanding of cancer immunosurveillance and immunoediting is essential. In this review, we discuss the fundamental knowledge of the phenomena and provide an overview of the next-generation immunotherapies in the pipeline.

Keywords: immune checkpoint inhibitors; immunoedition; immunotherapy; non-small cell lung cancer.

Figure 1

Cancer-immunity cycle: (1) Release of cancer antigens from tumor cells; (2) Presentation of cancer antigens on the major histocompatibility complex class (MHC) by antigen-presenting cells; (3) recognition of cancer antigens on the MHC by the T cell receptor, resulting in T cell activation; (4) Trafficking of activated T cells; (5) Infiltration into the tumor; (6) Recognition of cancer antigens on the MHC within the tumor; (7) Attack on tumor cells, resulting in tumor cell injury/death. This figure was adopted from Chen DS et al. [8].

Figure 2

Major co-stimulatory and co-suppression molecules involved in the priming phase of cancer immunity. The cancer antigen presented by antigen-presenting cells in the lymph nodes is recognized via the T cell antigen receptor (TCR) by cancer-specific T cells (signal 1, main signal). Major co-stimulatory and co-suppression molecules producing auxiliary stimuli (signal 2, sub-signal) during this step and their ligands are shown here. The signals reinforcing the immune responses to cancer are shown in red, while those the attenuation of these responses are shown in blue.

Figure 3

Major co-stimulatory and co-suppression molecules involved in the effector phase of cancer immunity. This figure shows major co-stimulatory and co-suppression molecules (involved in the attack against the cancer cells by activated and proliferated effector T cells after antigen presentation and recognition) and their ligands. The signals reinforcing the immune responses to cancer are shown in red, while the signals causing attenuation of such responses are shown in blue.

Figure 4

Tumor evolution and immunoediting. The accumulation of oncogenic mutations initiates tumor evolution. The immune surveillance system, including cytotoxic CD8 positive T cells, natural killer cells, and macrophages, recognize tumor-associated neoantigens presented by MHC molecules on antigen-presenting cells. The balance between signals from the tumor microenvironment and the immune system shifts during tumor elimination, equilibrium, and escape.

Figure 5

Tumor escape through human leukocyte antigen (HLA) loss. HLA loss allows tumor cells to escape the immune system. During tumor evolution, the accumulation of tumor neoantigens induces local immune infiltration. Tumor cells with HLA loss can be positively selected by avoiding CD8 T cell recognition.

Figure 6

Tumor antigens recognized by immune cells. Tumor antigens are categorized based on the pattern of gene expression. The production of antigenic peptides by cancer cells is illustrated herein. (A) Viral antigens are only expressed in virus-infected cells; (B) Differentiation antigens are encoded by genes with tissue-specific expression; (C) Cancer-germline genes are expressed in tumors or germ cells because of whole-genome demethylation; (D) Some genes are overexpressed in tumors owing to increased transcription or gene amplification. The resulting peptides are upregulated on these tumors, but also show a low level of expression in some noncancerous tissues; (E) However, mutated genes may yield a mutant peptide (neoantigen), which is recognized as nonself by immune cells. CEA, carcinoembryonic Ag; EGFR, epidermal growth factor receptor; EBV, Epstein-Barr virus; HPV, human papillomavirus; hTERT, human telomerase reverse transcriptase; MAGE-A3, melanoma-associated antigen 3; MART-1, melanoma antigen recognized by T cells-1; MCC, Merkel cell carcinoma. This figure is adapted from our previous article [63].

Figure 7

Foxp3+ T cell subset in the blood and tumor tissue. FoxP3^lowCD45RA+ naïve Treg (Fr. I) can be viewed as cells that have just been supplied from the thymus. If these naïve Treg are activated by the TCR signal, CD45RA becomes negative and FoxP3 is upregulated, yielding FoxP3^highCD45RA- effector Treg (Fr.II). Effector Treg (Fr. II) expresses high levels of CCR4. Regarding FoxP3+ cells, the CD45RA negative FoxP3^low CD4+ T cell (Fr. III) which has no immunosuppressive activity is not Treg, but a helper T cell producing IFN-γ or IL-17 when activated.

Figure 8

Roles of TAM in the tumor environment. TAM has the nature of M2-macrophage, directly suppressing the CTL, but also producing mediators involved in neovascularization, tumor infiltration/metastasis, and Treg migration/maintenance. The immunosuppressive activity is represented as a blue line and the tumor-stimulating activity as a red line.

Figure 9

Immune checkpoint structure between tumor cells and immune cells. Tumor antigens are presented to T cells via the interaction between the major histocompatibility complex and T cell receptors, which is the primary signal for activating T cells. Several sub-signals function as negative modulators of the immune response at different molecular checkpoints. (A) The cytotoxic T-lymphocyte associated protein 4 (CTLA-4) is induced in T cells at the time of the priming phase. CTLA-4 is expressed on the cell surface in proportion to the amount of antigen stimulation, and then CTLA-4 binds to CD80/86 with greater affinity than CD28, leading to specific T cell inactivation; (B) The binding of programmed cell death ligand 1 (PD-L1) to PD-1 prevents T cells from killing tumor cells in the body. Blocking the binding of PD-L1 to PD-1 with an immune checkpoint inhibitor allows the T cells to kill the tumor cells. This figure is adapted from our previous article [63].

Figure 10

Innate immune checkpoint. The intercellular signal CD47-SIRPα system, formed by the signal regulating protein (SIRP) α and membranous protein CD47 located in the cell membrane of macrophages with phagocytosing capability functions as an innate immune checkpoint. (A) If the SIRPα on macrophage binds to CD47 on cancer cells, the cancer cells release a phagocytosis avoidance signal for macrophages to escape phagocytosis; (B) If this checkpoint function is inhibited, the macrophage begins tumor cell phagocytosis.

Figure 11

Diagram for peptide vaccine. If a peptide vaccine originating from a cancer antigen is inoculated into a patient, the peptide is taken up by the DCs, resulting in the presentation of the antigen to the CTL. This antigenic stimulus induces proliferation and activation of CTL, resulting in specific injury/killing of the cancer cells presenting the cancer antigen peptide.

Figure 12

Adoptive transfer of autologous, antigen-loaded and activated DCs. Natural DC subsets and blood monocytes are isolated from blood and monocytes are cultured in vitro, differentiating into monocyte-derived DCs (MoDCs). After ex vivo activation and antigen loading, autologous DCs are reinfused into the patient to induce and activate antigen-specific T cells with strong efficacy and minimal side effects.

Figure 13

Cell therapy concept diagram (A) The Fab portion, corresponding to the surface antigen of the target tumor cell, is utilized in the form of single-chain antibody, and the signal transduction site (CD3ζ) of the T cell receptor and the CD28 (a co-stimulatory molecule for T cells) are fused to it, to yield CAR; (B) CAR is introduced by means of gene transfer with a retrovirus vector into T cell, to yield CAR-T cell. The T cell collected from the patient is genetically modified ex vivo, to yield CAR-T cell, which is infused into the patient after expanded culture.