Among several types of tumor, lung cancer is considered one of the most fatal and still the main cause of cancer-related deaths. Although chemotherapeutic agents can improve survival and quality of life compared with symptomatic treatment, cancers usually still progress after chemotherapy and are often aggravated by serious side effects. In the last few years there has been a growing interest in immunotherapy for lung cancer based on promising preliminary results in achieving meaningful and durable treatments responses with minimal manageable toxicity. This article is divided into two parts, the first part discusses the role of human immune system in controlling and eradicating cancer and the mechanisms of immune response evasion by tumor. The second part reviews the recent progress made in immunotherapy for lung cancer with results from trials evaluating therapeutic vaccines in addition to immune checkpoint blockade, specifically cytotoxic T lymphocyte associated protein 4, programmed death receptor 1 pathway, using monoclonal antibodies.

BackgroundOur previous studies have demonstrated that autophagosome-enriched vaccine (named DRibbles: DRiPs-containing blebs) induce a potent anti-tumor efficacy in different murine tumor models, in which DRibble-containing ubiquitinated proteins are efficient tumor-specific antigen source for the cross-presentation after being loaded onto dendritic cells. In this study, we sought to detect whether ubiquitinated proteins enriched from tumor cells could be used directly as a novel cancer vaccine.MethodsThe ubiquitin binding protein Vx3(A7) was used to isolate ubiquitinated proteins from EL4 and B16-F10 tumor cells after blocking their proteasomal degradation pathway. C57BL/6 mice were vaccinated with different doses of Ub-enriched proteins via inguinal lymph nodes or subcutaneous injection and with DRibbles, Ub-depleted proteins and whole cell lysate as comparison groups, respectively. The lymphocytes from the vaccinated mice were re-stimulated with inactivated tumor cells and the levels of IFN-γ in the supernatant were detected by ELISA. Anti-tumor efficacy of Ub-enriched proteins vaccine was evaluated by monitoring tumor growth in established tumor mice models. Graphpad Prism 5.0 was used for all statistical analysis.ResultsWe found that after stimulation with inactivated tumor cells, the lymphocytes from the Ub-enriched proteins-vaccinated mice secreted high level of IFN-γ in dose dependent manner, in which the priming vaccination via inguinal lymph nodes injection induced higher IFN-γ level than that via subcutaneous injection. Moreover, the level of secreted IFN-γ in the Ub-enriched proteins group was markedly higher than that in the whole cell lysate and Ub-depleted proteins. Interestingly, the lymphocytes from mice vaccinated with Ub-enriched proteins, but not Ub-depleted proteins and whole cell lysates, isolated from EL4 or B16-F10 tumor cells also produced an obvious level of IFN-γ when stimulated alternately with inactivated B16-F10 or EL4 tumor cells. Furthermore, Ub-enriched proteins vaccine showed a significant inhibitory effect on in vivo growth of homologous tumor, as well as allogeneic tumor, compared with Ub-depleted proteins and tumor cell lysate. Tumor growth was regressed after three times of vaccination with Ub-enriched proteins in contrast to other groups.ConclusionThese results indicated that Ub-enriched proteins isolated from tumor cells may have a potential as a potent vaccine for immunotherapy against cancer.

A simple and effective strategy was developed to enrich ubiquitinated proteins (UPs) from cancer cell lysate using the α-AlO nanoparticles covalently linked with ubiquitin binding protein (Vx3) (denoted as α-AlO-Vx3) via a chemical linker. The functionalized α-AlO-Vx3 showed long-term stability and high efficiency for the enrichment of UPs from cancer cell lysates. Flow cytometry analysis results indicated dendritic cells (DCs) could more effectively phagocytize the covalently linked α-AlO-Vx3-UPs than the physical mixture of α-AlO and Vx3-UPs (α-AlO/Vx3-UPs). Laser confocal microscopy images revealed that α-AlO-Vx3-UPs localized within the autophagosome of DCs, which then cross-presented α-AlO-Vx3-UPs to CD8 T cells in an autophagosome-related cross-presentation pathway. Furthermore, α-AlO-Vx3-UPs enhanced more potent antitumor immune response and antitumor efficacy than α-AlO/cell lysate or α-AlO/Vx3-UPs. This work highlights the potential of using the Vx3 covalently linked α-AlO as a simple and effective platform to enrich UPs from cancer cells for the development of highly efficient therapeutic cancer vaccines.

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A better understanding of the immune profile of non-small cell lung cancer (NSCLC) and the immunomodulatory impact of chemotherapy is essential to develop current therapeutic approaches . Herein, we collected p eripheral blood from 20 healthy donors and 50 patients with advanced NSCLC, before and after chemotherapy, followed by phenotypic analysis of lymphocyte subsets and assessment of the correlation between their post-chemotherapy levels and progression-free survival (PFS). Results showed that, before chemotherapy, the levels of CD8 + lymphocytes, PD-1 + CD4 + , Th2, and Th17 cells were elevated in patients’ peripheral blood, in contrast to natural killer (NK) cells and Th1 cells. Besides, there was no remarkable difference in the frequency of PD-1 + CD8 + cells between patients and healthy controls. After chemotherapy, the levels of CD8 + lymphocytes, NK, Th2, Th17, and Treg were declined, in contrast to the level of Th1 cells which was markedly increased. Importantly, chemotherapy had no impact on the frequencies of PD-1 + CD8 + and PD-1 + CD4 + cells. PFS was significantly better in patients with low percentage of PD-1 + CD4 + T cells than those with high percentage. Patients with high content of Th1 cells showed longer PFS than those with low content. The low percentages of Th17 and Treg cells were correlated with longer PFS, even though the difference did not reach statistical significance. In conclusion, the imbalance of lymphocyte subsets is a hallmark of NSCLC. Furthermore, the high level of PD-1 + CD4 + cells plays a crucial role in the progression of NSCLC and could be used as a prognostic marker; and the high level of Th1 could predict better clinical outcomes of chemotherapy.