PD-L1 immune suppression in cancer: Tumor cells or host cells?

Experimental cancer immunology and therap

PD-L1 expression on malignant cells is no prerequisite for checkpoint therapy

Experimental cancer immunology and therap

IL-6 signaling in macrophages is required for immunotherapy-driven regression of tumors

Background High serum interleukin (IL-6) levels may cause resistance to immunotherapy by modulation of myeloid cells in the tumor microenvironment. IL-6 signaling blockade is tested in cancer, but as this inflammatory cytokine has pleiotropic effects, this treatment is not always effective. Methods IL-6 and IL-6R blockade was applied in an IL-6-mediated immunotherapy-resistant TC-1 tumor model (TC-1.IL-6) and immunotherapy-sensitive TC-1.control. Effects on therapeutic vaccination-induced tumor regression, recurrence and survival as well on T cells and myeloid cells in the tumor microenvironment were studied. The effects of IL-6 signaling in macrophages under therapy conditions were studied in Il6ra(fl/fl)xLysM(cre+) mice. Results Our therapeutic vaccination protocol elicits a strong tumor-specific CD8(+) T-cell response, leading to enhanced intratumoral T-cell infiltration and recruitment of tumoricidal macrophages. Blockade of IL-6 signaling exacerbated tumor outgrowth, reflected by fewer complete regressions and more recurrences after therapeutic vaccination, especially in TC-1.IL-6 tumor-bearing mice. Early IL-6 signaling blockade partly inhibited the development of the vaccine-induced CD8(+) T-cell response. However, the main mechanism was the malfunction of macrophages during therapy-induced tumor regression. Therapy efficacy was impaired in Il6ra(fl/fl)xLysM(cre+) but not cre-negative control mice, while no differences in the vaccine-induced CD8(+) T-cell response were found between these mice. IL-6 signaling blockade resulted in decreased expression of suppressor of cytokine signaling 3, essential for effective M1-type function in macrophages, and increased expression of the phagocytic checkpoint molecule signal-regulatory protein alpha by macrophages. Conclusion IL-6 signaling is critical for macrophage function under circumstances of immunotherapy-induced tumor tissue destruction, in line with the acute inflammatory functions of IL-6 signaling described in infections.Experimental cancer immunology and therap

Photodynamic-Immune Checkpoint Therapy Eradicates Local and Distant Tumors by CD8(+) T Cells

Tumorimmunolog

PD-L1 immune suppression in cancer: Tumor cells or host cells?

Experimental cancer immunology and therap

Photodynamic cancer therapy enhances accumulation of nanoparticles in tumor-associated myeloid cells

In cancer treatment, nanomedicines may be employed in an attempt to improve the tumor localization of antineoplastic drugs e.g. immunotherapeutic agents either through passive or active targeting, thereby potentially enhancing therapeutic effect and reducing undesired off-target effects. However, a large number of administrated nanocarriers often fail to reach the tumor area. In the present study, we show that photodynamic therapy (PDT) enhances the tumor accumulation of systemically administered lipid-PEG layer coated poly (lactic-co-glycolic acid) (PLGA) nanoparticles (NP). Intravital microscopy and histological analysis of the tumor area reveal that the tumor vasculature was disrupted after PDT, disturbing blood flow and coinciding with entrapment of nanocarriers in the tumor area. We observed that the nanoparticles accumulating after treatment do not confine to specific locations within the tumor, but rather localize to various cells present throughout the tumor area. Finally, we show by flow cytometry that NP accumulation occurred mostly in immune cells of the myeloid lineage present in the tumor microenvironment (TME) as well as in tumor cells, albeit to a lower extent. These data expose opportunities for combination treatments of clinical PDT with NP-based immunotherapy to modulate the TME and improve antitumor immune responses.Imaging- and therapeutic targets in neoplastic and musculoskeletal inflammatory diseas

Targeting nanoparticles to CD40, DEC-205 or CD11c molecules on dendritic cells for efficient CD8(+) T cell response: A comparative study

Imaging- and therapeutic targets in neoplastic and musculoskeletal inflammatory diseas

Particulate Systems Based on Poly(Lactic-co-Glycolic)Acid (pLGA) for Immunotherapy of Cancer

Tumorimmunolog

PD-L1 expression on malignant cells is no prerequisite for checkpoint therapy

Experimental cancer immunology and therap

Polymeric nanoparticles for co-delivery of synthetic long peptide antigen and poly IC as therapeutic cancer vaccine formulation

Tumorimmunolog