No abstract

DDR1 has been identified as a cancer‐associated receptor tyrosine kinase that is highly expressed in several malignancies relative to normal tissues. Clinically approved multi‐kinase inhibitors, such as nilotinib, inhibit DDR1‐mediated tumor growth in xenograft models, suggesting DDR1 might be a potential target for cancer treatments. Here, we employed an antibody‐based strategy with a novel anti‐DDR1 antibody‐drug conjugate (ADC) for colon carcinoma treatment. We developed T 4 H 11 ‐DM4, an ADC targeting DDR1 which carries the tubulin inhibitor payload DM4. Immunohistochemical analysis of a tissue microarray containing 100 colon cancer specimens revealed that DDR1 was highly expressed in 81% of tumor tissues. Meanwhile, high expression of DDR1 was associated with poor survival in patients. In vitro , T 4 H 11 ‐DM4 exhibited potent anti‐proliferative activity with half maximal inhibitory concentration (IC 50 ) values in the nanomolar range in a panel of colon cancer cell lines. In vivo , the antitumor efficacy of T 4 H 11 ‐DM4 was evaluated in three colon cancer cell lines expressing different levels of DDR1. T 4 H 11 ‐DM4 achieved complete tumor regression at doses of 5 and 10 mg·kg −1 in HT‐29 and HCT116 tumor models. Moreover, a correlation between in vivo efficacy of T 4 H 11 ‐DM4 and the levels of DDR1 expression on the cell surface was observed. Tumor cell proliferation was caused by the induction of mitotic arrest, indicating that the antitumor effect in vivo was mediated by DM4. In addition, T 4 H 11 ‐DM4 was efficacious in oxaliplatin‐resistant colon cancer models. In exploratory safety studies, T 4 H 11 ‐DM4 exhibited no overt toxicities when multi‐doses were administered at 10 mg·kg −1 into BALB/c nude mice or when a single dose up to 50 mg·kg −1 was administered into BALB/c mice. Overall, our findings highlight the potential of DDR1‐targeted ADC and may facilitate the development of a new effective therapeutic strategy for colon cancer.

Immune checkpoint inhibitors have achieved unprecedented success in cancer immunotherapy. However, the overall response rate to immune checkpoint inhibitor therapy for many cancers is only between 20 and 40%, and even less for colorectal cancer (CRC) patients. Thus, there is an urgent need to develop an efficient immunotherapeutic strategy for CRC. Here, we developed a novel CRC combination therapy consisting of a multiple receptor tyrosine kinase inhibitor (Foretinib) and anti-PD-1 antibody. The combination therapy significantly inhibited tumor growth in mice, led to improved tumor regression without relapse (83% for CT26 tumors and 50% for MC38 tumors) and prolonged overall survival. Mechanistically, Foretinib caused increased levels of PD-L1 via activating the JAK2-STAT1 pathway, which could improve the effectiveness of the immune checkpoint inhibitor. Moreover, the combination therapy remodeled the tumor microenvironment and enhanced anti-tumor immunity by further increasing the infiltration and improving the function of T cells, decreasing the percentage of tumor-associated macrophages (TAMs) and inhibiting their polarization toward the M2 phenotype. Furthermore, the combination therapy inhibited the metastasis of CT26-Luc tumors to the lung in BALB/c mouse by reducing proportions of regulatory T-cells, TAMs and M2 phenotype TAMs in their lungs. This study suggests that a novel combination therapy utilizing both Foretinib and anti-PD-1 antibody could be an effective combination strategy for CRC immunotherapy.

Actinomycetes in extreme alpine habitat have attracted much attention due to their unique physiological activities and functions. However, little is known about their ecological distribution and diversity. Here, we explored the phylogenetic relationship and physiological heterogeneity of cultivable actinomycetes from near-root soils of different plant communities in the Laohu Ditch (2200 – 4200 m) and Gaize County area (5018 – 5130 m) on the Qinghai-Tibetan Plateau. A total of 128 actinomycete isolates were obtained, 16S rDNA-sequenced and examined for antimicrobial activities and organic acid, H 2 S, diffusible pigments, various extracellular enzymes production. Seventy three isolates of the total seventy eight isolates from the Laohu Ditch, frequently isolated from 2200 to 4200 m, were closely related to Streptomyces spp. according to the 16S rDNA sequencing, while four isolates within the genus Nocardia spp. were found at 2200, 2800, and 3800 m. In addition, one potential novel isolate with 92% sequence similarity to its nearest match Micromonospora saelicesensis from the GenBank database, was obtained at 2200 m. From the Gaize County area, fifty Streptomyces isolates varied in diversity at different sites from 5018 to 5130 m. The investigation of phenotypic properties of 128 isolates showed that 94.5, 78.9, 68, 64.8, 53, 51.6, 50, 36.7, 31.2, and 22.7% of the total isolates produced catalase, lipase 2, urease, protease, H 2 S, lipase 3, amylase, lipase 1, diffusible pigment and organic acid, respectively. The antimicrobial assays of the total isolates revealed that 5, 28, 19, and 2 isolates from Streptomyces spp. exhibited antimicrobial activity against Escherichia coli , Staphylococcus aureus , Candida albicans , and Pseudomonas aeruginosa , respectively. This study intends to bring helpful insights in the exploitation and utilization of alpine actinomycetes for novel bioactive compounds discovery.

Ovarian cancer is considered to be the most lethal gynecologic malignancy, and despite the development of conventional therapies and new therapeutic approaches, the patient's survival time remains short because of tumor recurrence and metastasis. Therefore, effective methods to control tumor progression are urgently needed. The oncofetal tumor‐associated antigen 5T4 (trophoblast glycoprotein, TPBG) represents an appealing target for adoptive T‐cell immunotherapy as it is highly expressed on the surface of various tumor cells, has very limited expression in normal tissues, and spreads widely in malignant tumors throughout their development. In this study, we generated second‐generation human chimeric antigen receptor (CAR) T cells with redirected specificity to 5T4 (5T4 CAR‐T) and demonstrated that these CAR‐T cells can elicit lytic cytotoxicity in targeted tumor cells, in addition to the secretion of cytotoxic cytokines, including IFN‐γ, IL‐2, and GM‐CSF. Furthermore, adoptive transfer of 5T4 CAR‐T cells significantly delayed tumor formation in xenografts of peritoneal and subcutaneous animal models. These results demonstrate the potential efficacy and feasibility of 5T4 CAR‐T cell immunotherapy and provide a theoretical basis for the clinical study of future immunotherapies targeting 5T4 for ovarian cancer.