Virotherapy-recruited PMN-MDSC infiltration of mesothelioma blocks antitumor CTL by IL-10-mediated dendritic cell suppression

Abstract

Antitumor cytotoxic T lymphocytes (CTLs) are essential for immune surveillance, yet the blockade of eliciting such CTLs during oncolytic virotherapy remains incompletely understood. Here, we show that oncolysis of mesothelioma by modified vaccinia Tiantan (MVTT) induces damage-associated molecular patterns exposure. Although MVTT leads to regression of established mesothelioma dose-dependently, antitumor CTLs are rarely induced. Mechanistically, MVTT virotherapy generates C-X-C chemokines that recruit CXCR2-expressing polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) into tumor microenvironment, where they suppress dendritic cells (DCs) by producing IL-10 and halt CTL responses. During the virotherapy, however, depletion of PMN-MDSCs but not of monocytic (M)-MDSCs results in the induction of potent antitumor CTLs that not only eradicate established mesothelioma but also prevent the second tumor challenge. Our findings suggest that vaccinia virotherapy may combine strategies that prevent the chemotactic recruitment of PMN-MDSCs, block their suppression on DCs or deplete PMN-MDSCs in order to induce potent CTLs for tumor eradication.

Mechanisms of immune suppression by myeloid-derived suppressor cells: the role of interleukin-10 as a key immunoregulatory cytokine

“…[ 146 ] have reported that endostatin can achieve such goals in lung cancer by limiting the recruitment of MDSCs and decreasing the production of anti-inflammatory cytokines, including IL-10 among others. Consistent with this view, Tan et al [ 147 ] have shown that depletion of MDSCs, particularly IL-10-producing PMN-MDSCs, which can inhibit DCs that activate anti-tumour cytotoxic T cell responses, can enhance the therapeutic efficacy of modified vaccinia Tiantan strain by inducing anti-tumour cytotoxic T cell responses in mesothelioma. Treatment with zoledronic acid impaired the accumulation of MDSCs to the tumour site resulting in delayed tumour growth rate, and increased recruitment of T cells to the tumour and prolonged the overall survival [ 148 ].…”

Connecting METTL3 and intratumoural CD33+ MDSCs in predicting clinical outcome in cervical cancer

“…Some studies have shown that METTL3 expression can promote tumour cell proliferation, leading to poor patient prognosis. The tumour-infiltrated MDSC population usually induces antitumour immunity tolerance by inhibiting the proliferation and function of T cells, such as hindering antigen presentation by antigen-presenting cells [ 36 ]. Increased METTL3 levels and CD33 + MDSCs have been found in tumour microenvironments and lead to a poor prognosis [ 37 – 40 ].…”

Connecting METTL3 and intratumoural CD33+ MDSCs in predicting clinical outcome in cervical cancer

“…Some studies have shown that METTL3 expression can promote tumour cell proliferation, leading to poor patient prognosis. The tumour-in ltrated MDSC population usually induces antitumour immunity tolerance by inhibiting the proliferation and function of T cells, such as hindering antigen presentation by antigen-presenting cells (36). Increased METTL3 levels and CD33 + MDSCs have been found in tumour microenvironments and lead to a poor prognosis (37)(38)(39)(40).…”