Depletion of phagocytic myeloid cells triggers spontaneous T cell- and NK cell-dependent antitumor activity

Abstract

Depletion of tumor associated macrophages and inhibition of tumor angiogenesis have been invoked as the principle mechanisms underlying the antitumor activity of liposomal clodronate (LC). However, previous studies have not examined the effects of LC on systemic antitumor immunity. Here, we used mouse tumor models to elucidate the role of T and NK cells in the antitumor activity elicited by the systemic administration of LC. Strikingly, we found that the antitumor activity of LC is completely abolished in immunodeficient Rag1−/− mice. Moreover, both Cd4−/− and Cd8−/− mice as well as mice depleted of NK cells manifested a significant impaired ability to control tumor growth following LC administration. Treatment with LC did not result in an overall increase in T- or NK-cell numbers in tumors or lymphoid organs, nor was tumor infiltration with T or NK cells altered. However, T and NK cells isolated from the spleen of LC-treated mice exhibited significant increased tumor-specific secretion of interferon γ and interleukin 17 and greater cytolytic activity. We concluded that the antitumor effects of LC are largely dependent on the generation of systemic T-cell and NK- cell activity, most likely owing to the depletion of immune suppressive myeloid cell populations in lymphoid tissues. These findings suggest that the systemic administration of LC may constitute an effective means for non-specifically augmenting the antitumor activity of T and NK cells.

Reshaping Intratumoral Mononuclear Phagocytes with Antibody‐Opsonized Immunometabolic Nanoparticles

“…The anti-CD163 antibody-opsonized immeNPs, assembled from fluorescein (FAM)-incorporated MSNs (CTS/p(I:C)-M FAM MA), exhibited significantly higher uptake efficiency in the Raw264.7 macrophages than their undecorated version (CTS/p(I:C)-M FAM M) (Figure S11b, Supporting Information). In the mice bearing orthotopic 4T1 TNBC, we observed that the tumor-infiltrating TAMs and DCs prominently upregulated their CD163 expression compared to other cells in the tumor tissue (Figure S12a [53,54] Consistent with previous studies, clodronate showed a mild inhibitory effect on tumor growth, suggesting the pro-tumor activities of MPs in the immunosuppressive TME. [55] The immeNPs could not further restrict tumor growth in clodronate-treated mice, indicating that the anti-tumor effects of CTS/p(I:C)-MMA relied on MP reprogramming (Figure S15, Supporting Information).…”

Depletion of tumor-associated macrophages enhances the anti-tumor immunity induced by a Toll-like receptor agonist-conjugated peptide

“…Clodronate depletes not only macrophages but also CD11b C Gr-1 C myeloid-derived suppressor cells (MDSCs). 44 Although we did not find any significant decrease in the numbers of MDSCs in this tumor model post-inoculation (data not shown), Pam2IDG immunization combined with clodronate induced antigen-specific CTLs to the same degree as Pam2IDG alone (Fig. 5D).…”

A Role for Dogs in Advancing Cancer Immunotherapy Research

“…Each of these tumor models in dogs therefore offers the opportunity for evaluation of agents that target the TME, particularly for those designed to remove immune suppressive cells to help activate immunologically "cold" tumors. For example, depleting target tumor-associated macrophages by administration of agents such as liposomal clodronate that deplete tumor macrophages outright has been evaluated in dogs (51,61). We also found that modifying the TME by direct tumor transfection with a potent T cell activating molecule such as a bacterial superantigen could stimulate T cell infiltration and activation and significant tumor regression in dogs with melanoma [ Figure 1; (56)].…”