Inhibition of tumor‐associated macrophages by trabectedin improves the antitumor adaptive immunity in response to anti‐PD‐1 therapy

Abstract

A considerable proportion of cancer patients are resistant or only partially responsive to immune checkpoint blockade immunotherapy. Tumor-Associated Macrophages (TAMs) infiltrating the tumor stroma suppress the adaptive immune responses and, hence, promote tumor immune evasion. Depletion of TAMs or modulation of their protumoral functions is actively pursued, with the purpose of relieving this state of immunesuppression. We previously reported that trabectedin, a registered antitumor compound, selectively reduces monocytes and TAMs in treated tumors. However, its putative effects on the adaptive immunity are still unclear. In this study, we investigated whether treatment of tumor-bearing mice with trabectedin modulates the presence and functional activity of T-lymphocytes. In treated tumors, there was a significant upregulation of T cellassociated genes, including CD3, CD8, perforin, granzyme B, and IFN-responsive genes (MX1, CXCL10, and PD-1), indicating that T lymphocytes were activated after treatment. Notably, the mRNA levels of the Pdcd1 gene, coding for PD-1, were strongly increased. Using a fibrosarcoma model poorly responsive to PD-1-immunotherapy, treatment with trabectedin prior to anti-PD-1 resulted in improved antitumor efficacy. In conclusion, pretreatment with trabectedin enhances the therapeutic response to checkpoint inhibitorbased immunotherapy. These findings provide a good rational for the combination of trabectedin with immunotherapy regimens.

Antitumor Potential of Immunomodulatory Natural Products

“…Trabectidin, a tetrahydroisoquinoline alkaloid that was initially isolated from the Caribbean tunicate Ecteinascida turbinata with the name of ET-743 [198,199], has been the first marine-derived anti-neoplastic drug approved for the treatment of advanced soft tissue sarcoma and, in combination with pegylated liposomal doxorubicin, for the treatment of patients with relapsed platinum-sensitive ovarian cancer. The alkaloid besides the cytotoxic effect has immunomodulatory activity on several cell types of the microenvironment [200]. Several studies have also underlined that Trabectedin is an immunomodulatory drug with potential use in enhancing the therapeutic response to checkpoint inhibitor-based immunotherapy and in overcoming chemoimmune resistance [200,201] Stimulation of cytokine production [193,194] Abbreviations: AP-1, activator protein 1; NF-kB, nuclear factor kappa of activated B cells; CD, cluster of differentiation; IL-8, interleukin 8; NK, natural killer; Th1, T helper 1; Th2, T helper 2; DC, dendridic cell; PCK, Protein kinase C.…”

Effects of the Anti-Tumor Agents Trabectedin and Lurbinectedin on Immune Cells of the Tumor Microenvironment

“…Recent studies specifically investigated the potential of trabectedin to modulate T lymphocytes in mouse cancer models. Analyses of tumor tissue in trabectedin-treated mice revealed a greater number of CD3+ and CD8+ lymphocytes by flow cytometry and immunohistochemistry ( 58 ). mRNA expression of several T cell-associated genes were significantly up-regulated after trabectedin, including the cytotoxic molecules granzyme B and perforin, the anti-tumor cytokine IFN γ and IFN-responsive genes such as MX1, CXCL10 and the checkpoint molecule PD-1 ( 58 ).…”

“…Analyses of tumor tissue in trabectedin-treated mice revealed a greater number of CD3+ and CD8+ lymphocytes by flow cytometry and immunohistochemistry ( 58 ). mRNA expression of several T cell-associated genes were significantly up-regulated after trabectedin, including the cytotoxic molecules granzyme B and perforin, the anti-tumor cytokine IFN γ and IFN-responsive genes such as MX1, CXCL10 and the checkpoint molecule PD-1 ( 58 ). These findings strongly indicate an activation of the T cell-mediated immune response upon macrophage targeting by trabectedin.…”

“…Based on this finding, it was of interest to investigate whether the combination of trabectedin with anti-PD-1 checkpoint inhibitors improved the response to immunotherapy. Combination of trabectedin and anti-PD-1 showed increased efficacy in osteosarcoma and ovarian cancer mouse models ( 33 , 59 ); using a mouse fibrosarcoma poorly responding to anti-PD-1 alone, an improved anti-tumor response was achieved when mice were pre-treated with trabectedin ( 58 ); in another study, depletion of myeloid cells combined with chemotherapy and PD-1 blockade, synergistically inhibited the progression of a murine leukemia ( 38 ).…”

“…In the fibrosarcoma model ( 58 ), an important aspect that emerged was the correct timing of the combination trabectedin and checkpoint immunotherapy. It was found that the best protocol was a sequential treatment (trabectedin first, followed by anti-PD-1), rather than a simultaneous administration.…”