Treatment with lentiviral vectors encoding shRNA against interleukin 10 modulates the immunosuppressive activity of murine colon carcinoma‑associated myeloid‑derived suppressor cells

Abstract

Myeloid-derived suppressor cells (MDSCs) are potent suppressors of antitumor immunity and their accumulation is often associated with poor prognosis. The aim of the present study was to determine the mechanisms of action of lentiviral vectors encoding short hairpin (sh)RNA against interleukin-10 (IL-10), with particular emphasis on their influence on the activity of tumor-derived MDSCs. Lentiviral vectors encoding shRNA against IL-10 (shIL-10 LVs) were utilized to silence the expression of IL-10 either in MDSCs that were generated ex vivo from bone marrow cells cultured in the presence of supernatant from MC38 colon carcinoma cells, or in situ in the MC38 murine colon carcinoma environment. Although monocytic MDSCs (M-MDSCs) transduced with shIL-10 LVs exhibited increased suppressor activity, transduction of polymorphonuclear MDSCs (PMN-MDSCs) appeared to reduce their ability to inhibit T lymphocyte functions. Analysis of EGFP expression in MC38 tumors revealed that intratumorally inoculated shIL-10 LVs transduced tumor-infiltrating myeloid cells with the highest efficiency and, led to a decreased IL-10 level in the tumor microenvironment. However, the effect was accompanied by increased influx of PMN-MDSCs into tumors observed both on the 6th and on the 10th day after shIL-10 LV injections. Nevertheless, it was noted that suppressor activity of myeloid cells isolated from tumors was dependent on the efficiency of tumor-derived PMN-MDSC transduction with shIL-10 LVs. The increased percentage of transduced PMN-MDSCs on the 10th day was associated with diminished immunosuppressive activity of tumor-derived myeloid cells and an elevated ratio of cytotoxic T lymphocytes to M-MDSCs. The obtained data indicated that treatment with shIL-10 LVs may result in modulation of the immunosuppressive activity of MC38 colon carcinoma-derived MDSCs.

Inhibition of MC38 colon cancer growth by multicomponent chemoimmunotherapy with anti-IL-10R antibodies, HES-MTX nanoconjugate, depends on application of IL-12, IL-15 or IL-18 secreting dendritic cell vaccines

“…This can be achieved by local or systemic blockade of IL-10 activity, e.g. by administration of shRNA against IL-10 and antibodies neutralizing IL-10 or IL-10 receptor ( 19 – 24 ). The temporary blockade of the IL-10-specific receptor (IL-10R) with anti-IL-10R antibodies reduces the sensitivity of immune cells to IL-10, which prevents the transformation of effector cells into suppressor cells and prepares optimal conditions for triggering an efficient anticancer response.…”

The GDF11 Promotes Nerve Regeneration After Sciatic Nerve Injury in Adult Rats by Promoting Axon Growth and Inhibiting Neuronal Apoptosis

“…To find a more effective treatment strategy for sciatic nerve injury, our study confirmed the protective effect of GDF11 on neurons in vitro , and in a further study, we used a lentiviral vector to induce GDF11 overexpression and thus create and maintain a local microenvironment conducive to nerve regeneration. Lentivirus is a safe in vivo expression vector that is currently widely used ( Anger-Gora et al, 2021 ; Reyne et al, 2021 ). Specifically, we found that lentivirus can transfer the GDF11 gene into the peripheral nervous system and overexpress GDF11 to continuously produce a large amount of GDF11 locally and thus promote the recovery of nerve function after peripheral nerve transection.…”