Abstract Programmed cell death protein 1/programmed cell death ligand 1 (PD-1/PD-L1) blockade are standard of care for many patients with advanced or metastatic cancer. However, a majority of patients remain resistant to these treatments. It has been reported that local oncolytic viral infection of tumors is capable of overcoming systemic resistance to PD-1 blockade, and strongly suggest the combination therapy of virotherapy with PD-1 blockade to improve therapeutic efficacy in tumors that are refractory to checkpoint blockade. We investigate the antitumor effects of an E1B55KD deleted oncolytic adenovirus H101, in combination with a humanized anti-PD-1 monoclonal antibody Camrelizumab on cancer. Combination of H101 with Camrelizumab demonstrated more potent antitumor effects than monotherapy in immune system humanized NSG mice subcutaneous (S.C.) tumor model. Increased tumor infiltrating T cells including the total and IFN-γ-expressing CD8 + T cells in the combination treatment group were observed. H101 infection induced decreased expression of CD47 on cancer cells, thereby promoting macrophage to phagocytose cancer cells. With the activation of macrophage by H101, increased levels of cytokines including TNF, IL-12 and IFN-γ were observed when induced THP-1 cells were co-cultured with H101-treated cancer cells, which further induced increased expressions of IFN-γ in T cells. Eliminating the IL-12 by anti-IL-12 neutralizing antibodies abolished IFN-γ production from T cells, showing activation of macrophages by H101 induced oncolysis to promote IFN-γ secretion of T cells via IL-12. Meanwhile, infection with H101 induced upregulation of PD-L1 on YTS-1 cells. These results suggested that H101 works synergistically to enhance therapeutic efficacy of PD-1 blockade on cancer by suppressing CD47 signaling, which may promote phagocytose of macrophages to tumor cells and activate CD8 + T cells. Combination of H101 with PD-1 blockade would be a novel strategy for treating cancer.
Background Lung metastasis remains the primary cause of tumor-related mortality, with limited treatment options and unsatisfactory efficacy. In preclinical studies, T helper 9 (T H 9) cells have shown promise in treating solid tumors. However, it is unclear whether T H 9 cells can tackle more challenging situations, such as established lung metastases. Moreover, comprehensive exploration into the nuanced biological attributes of T H 9 cells is imperative to further unravel their therapeutic potential. Methods We adoptively transferred T H 1, T H 9, and T H 17 cells into subcutaneous, in situ , and established lung metastases models of osteosarcoma and triple-negative breast cancer, respectively, comparing their therapeutic efficacy within each distinct model. We employed flow cytometry and an in vivo imaging system to evaluate the accumulation patterns of T H 1, T H 9, and T H 17 cells in the lungs after transfusion. We conducted bulk RNA sequencing on in vitro differentiated T H 9 cells to elucidate the chemokine receptor CXCR4, which governs their heightened pulmonary tropism relative to T H 1 and T H 17 cell counterparts. Using Cd4 cre Cxcr4 flox/flox mice, we investigate the effects of CXCR4 on the lung tropism of T H 9 cells. We performed mass spectrometry to identify the E3 ligase responsible for CXCR4 ubiquitination and elucidated the mechanism governing CXCR4 expression within T H 9 cellular milieu. Ultimately, we analyzed the tumor immune composition after T H 9 cell transfusion and evaluated the therapeutic efficacy of adjunctive anti-programmed cell death protein-1 (PD-1) therapy in conjunction with T H 9 cells. Results In this study, we provide evidence that T H 9 cells exhibit higher lung tropism than T H 1 and T H 17 cells, thereby exhibiting exceptional efficacy in combating established lung metastases. CXCR4-CXCL12 axis is responsible for lung tropism of T H 9 cells as ablating CXCR4 in CD4 + T cells reverses their lung accumulation. Mechanistically, tumor necrosis factor receptor-associated factor 6 (TRAF6)-driven hyperactivation of NF-κB signaling in T H 9 cells inhibited ITCH-mediated ubiquitination of CXCR4, resulting in increased CXCR4 accumulation and enhanced lung tropism of T H 9 cells. Besides, T H 9 cells’ transfusion significantly improved the immunosuppressed microenvironment. T H 9 cells and anti-PD-1 exhibit synergistic effects in tumor control. Conclusions Our findings emphasized the innate lung tropism of T H 9 cells driven by the activation of TRAF6, which supports the potential of T H 9 cells as a promising therapy for established lung metastases.
Abstract TGF-β is essential for inducing systemic tumor immunosuppression; thus, blocking TGF-β can greatly enhance antitumor immunity. However, there are still no effective TGF-β inhibitors in clinical use. Here, we show that the clinically approved compound ursodeoxycholic acid (UDCA), by degrading TGF-β, enhances antitumor immunity through restraining Treg cell differentiation and activation in tumor-bearing mice. Furthermore, UDCA synergizes with anti-PD-1 to enhance antitumor immunity and tumor-specific immune memory in tumor-bearing mice. UDCA phosphorylates TGF-β at T282 site via TGR5-cAMP-PKA axis, causing increased binding of TGF-β to carboxyl terminus of Hsc70-interacting protein (CHIP). Then, CHIP ubiquitinates TGF-β at the K315 site, initiating p62-dependent autophagic sorting and subsequent degradation of TGF-β. Notably, results of retrospective analysis shows that combination therapy with anti-PD-1 or anti-PD-L1 and UDCA has better efficacy in tumor patients than anti-PD-1 or anti-PD-L1 alone. Thus, our results show a mechanism for TGF-β regulation and implicate UDCA as a potential TGF-β inhibitor to enhance antitumor immunity.
Doxorubicin (Dox) is an anti-tumor drug with a broad spectrum, whereas the cardiotoxicity limits its further application. In clinical settings, liposome delivery vehicles are used to reduce Dox cardiotoxicity. Here, we substitute extracellular vesicles (EVs) for liposomes and deeply investigate the mechanism for EV-encapsulated Dox delivery. The results demonstrate that EVs dramatically increase import efficiency and anti-tumor effects of Dox in vitro and in vivo, and the efficiency increase benefits from its unique entry pattern. Dox-loading EVs repeat a "kiss-and-run" motion before EVs internalization. Once EVs touch the cell membrane, Dox disassociates from EVs and directly enters the cytoplasm, leading to higher and faster Dox import than single Dox. This unique entry pattern makes the adhesion between EVs and cell membrane rather than the total amount of EV internalization the key factor for regulating the Dox import. Furthermore, we recognize ICAM1 as the molecule mediating the adhesion between EVs and cell membranes. Interestingly, EV-encapsulated Dox can induce ICAM1 expression by irritating IFN-γ and TNF-α secretion in TME, thereby increasing tumor targeting of Dox-loading EVs. Altogether, EVs and EV-encapsulated Dox synergize via ICAM1, which collectively enhances the curative effects for tumor treatment.
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