Myeloid-derived suppressor cells (MDSCs) are a heterogenic population of immature myeloid cells with immunosuppressive effects, which undergo massive expansion during tumor progression. These cells not only support immune escape directly but also promote tumor invasion via various non-immunological activities. Besides, this group of cells are proved to impair the efficiency of current antitumor strategies such as chemotherapy, radiotherapy, and immunotherapy. Therefore, MDSCs are considered as potential therapeutic targets for cancer therapy. Treatment strategies targeting MDSCs have shown promising outcomes in both preclinical studies and clinical trials when administrated alone, or in combination with other anticancer therapies. In this review, we shed new light on recent advances in the biological characteristics and immunosuppressive functions of MDSCs. We also hope to propose an overview of current MDSCs-targeting therapies so as to provide new ideas for cancer treatment.

No abstract

The tumoricidal efficiency of human CART cells is generally evaluated using immune-deficient mouse models; however, due to their immune-incompetency and the species-specific reactivity of a target antigen, these models are problematic to imitate CART induced adverse effects in the clinic. Epithelial cell adhesion molecule (EpCAM) is a tumor-associated antigen overtly presented on the cell surface of various carcinomas, making it an attractive target for CART therapy. Here, we developed an anti-mouse EpCAM CAR to evaluate its safety and efficacy in immunocompetent mouse models. As previously reported for their human equivalents, murine EpCAM CART cells exhibit promising anti-tumor efficacy in vitro and in vivo. However, after CART infusion, various dose-depended toxicities including body weight loss, cytokine-release syndrome (CRS), and death were observed in both tumor-bearing and tumor-free mice. Pathological examination revealed unexpected and severe pulmonary immunopathology due to basal EpCAM expression in normal lung. While our study validates EpCAM CAR-T's potent antitumor efficacy, it also reveals that EpCAM CART cells used for the treatment of solid tumors may cause lethal toxicity and should, therefore, be evaluated in patients with caution.

BackgroundIn recent years, lung cancer incidence has been increasing; however the impact of different histological types of lung cancer is not yet clear.MethodsTrends in the lung cancer incidence rate by histological type were examined based on data of 36 658 primary lung cancer patients from West China Hospital between 1995 and 2015.ResultsThe most common histological type of lung cancer in our hospital was adenocarcinoma (ADC) in both genders, followed by squamous cell carcinoma (SQCC), and small cell carcinoma (SCLC), which is consistent with general worldwide trends. The proportion of young patients with SCLC showed a downward trend. In the overall population with lung cancer, the number of elderly patients with lung cancer increased significantly, while the proportion of elderly patients increased gradually. The mean age at diagnosis also increased. The number of women with ADC increased sharply in recent years, especially in young patients, and the incidence rate in women is now greater than in men.ConclusionSignificant increases in the number of patients with ADC and the rate of lung cancer in women over recent years were observed, indicating that research on the pathogenesis of disease in these patients is urgent.

Pleural and peritoneal metastasis accompanied by malignant pleural effusion (MPE) or malignant ascites (MA) is frequent in patients with advanced solid tumors that originate from the lung, breast, gastrointestinal tract and ovary. Regional delivery of CAR-T cells represents a new strategy to control tumor dissemination in serous cavities. However, malignant effusions constitute an immune-suppressive environment that potentially induces CAR-T cell dysfunction. Here, we demonstrated that the anti-tumor cytotoxicity of conventional 2nd-generation CAR-T cells was significantly inhibited by both the cellular and non-cellular components of MPE/MA, which was primarily attributed to impaired CAR-T cell proliferation and cytokine production in MPE/MA environment. Interestingly, we found that PD-L1 was widely expressed on freshly-isolated MPE/MA cells. Based on this feature, a novel PD-L1-targeting chimeric switch receptor (PD-L1.BB CSR) was designed, which can bind to PD-L1, switching the inhibitory signal into an additional 4-1BB signal. When co-expressed with a 2nd-generation CAR, PD-L1.BB CSR-modified CAR-T cells displayed superior fitness and enhanced functions in both culture medium and MPE/MA environment, causing rapid and durable eradication of pleural and peritoneal metastatic tumors in xenograft models. Further investigations revealed elevated expressions of T-cell activation, proliferation, and cytotoxicity-related genes, and we confirmed that PD-L1 scFv and 4-1BB intracellular domain, the two important components of PD-L1.BB CSR, were both necessary for the functional improvements of CAR-T cells. Overall, our study shed light on the clinical application of PD-L1.BB CSR-modified dual-targeting CAR-T cells. Based on this study, a phase I clinical trial was initiated in patients with pleural or peritoneal metastasis (NCT04684459).

e20558 Background: With the recommendation of high-resolution chest computed tomography scan in lung cancer screening, multiple primary lung cancers (MPLC) is gaining more attention. Identifying MPLC from intrapulmonary metastases (IPM) is crucial to the clinical management. The current guidelines for the identification are always based on expert consensus rather than clinical evidence. We aim to develop a reliable identification method and further figure out the clinical and genetic features of MPLC. Methods: We retrospectively screened 305 lung lesions from 131 patients who underwent radical resection for multiple lung carcinomas. To minimize the effect of therapeutic intervention on prognostic outcomes, patients with each single tumor size smaller than 4cm, free of nodal or systemic metastases, and had high-quality whole-exon sequencing (WES) data were included. We selected 11 patients with confirmed intrapulmonary metastases for training. All patients’ follow-up information was collected until disease recurrence or metastases. A WES genetic divergence method for identifying MPLC from IPM was developed. The disease-free survival (DFS) was used as a validation tool for identification reliability. Results: A total of 61 eligible multi-lesion patients with 128 resected non-small cell lung cancer (NSCLC) lesions were finally analyzed. Based on WES genetic divergence identification, 51 MPLC patients were identified, whose DFS was significantly prolonged (HR, 0.27; 95% CI, 0.08 to 0.91; P = 0.02), while other recommended methods for identifying MPLC patients failed to show a DFS advantage. Among MPLC patients, 43.1% (22/51) had a first-degree relatives cancer family history, of whom 54.5% (12/22) had a lung cancer family history. EGFR was still the most common mutation gene (72.5%, 37/51); however, TP53 mutations was less frequent in MPLC (21% vs. 48%, P < 0.05), and tumor mutation burden (TMB) was lower (median, 0.73 muts/Mb vs. 1.15 muts/Mb, P < 0.01). Notably, despite the lack of shared alterations, unique germline variants in cancer-predisposing genes, particularly nonsynonymous SNV in solute carrier gene (SLC) family, were observed in most MPLC patients, rarely overlapping with IPM patients. Conclusions: WES-based genetic divergence clearly distinguishes independent primary tumors from IPM in NSCLC patients. MPLC patients represent a unique population which deserves further study.

Tumor immunotherapy brings substantial and long-term clinical benefits that can even cure tumors. However, the accumulation of evidence suggests that immunotherapy also induces severe and complex neurologic immune-related adverse events (ir-AEs) and even leads to immunotherapy-related death, which arouses the concern of clinicians. The timely and accurate identification of neurotoxicity helps clinicians detect and treat these complications early, thereby enhancing treatment efficiency and improving the prognosis of patients. At present, the mechanism of neurotoxicity caused by immunotherapy has not been completely elucidated. This paper mainly reviews the clinical features, pathogenesis, and therapeutic strategies of neurologic ir-AEs.

No abstract