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

Abstract

Immune cells in the tumor micro-environment (TME) establish a complex relationship with cancer cells and may strongly influence disease progression and response to therapy. It is well established that myeloid cells infiltrating tumor tissues favor cancer progression. Tumor-Associated Macrophages (TAMs) are abundantly present at the TME and actively promote cancer cell proliferation and distant spreading, as well as contribute to an immune-suppressive milieu. Active research of the last decade has provided novel therapeutic approaches aimed at depleting TAMs and/or at reprogramming their functional activities. We reported some years ago that the registered anti-tumor agent trabectedin and its analogue lurbinectedin have numerous mechanisms of action that also involve direct effects on immune cells, opening up new interesting points of view. Trabectedin and lurbinectedin share the unique feature of being able to simultaneously kill cancer cells and to affect several features of the TME, most notably by inducing the rapid and selective apoptosis of monocytes and macrophages, and by inhibiting the transcription of several inflammatory mediators. Furthermore, depletion of TAMs alleviates the immunosuppressive milieu and rescues T cell functional activities, thus enhancing the anti-tumor response to immunotherapy with checkpoint inhibitors. In view of the growing interest in tumor-infiltrating immune cells, the availability of antineoplastic compounds showing immunomodulatory effects on innate and adaptive immunity deserves particular attention in the oncology field.

Immunometabolic actions of trabectedin and lurbinectedin on human macrophages: Relevance for their antitumor activity

“…From a therapeutic point of view, different groups attributed the antitumor effects of TRB and LUR to the fact that these molecules exert a "tropism" for mononuclear phagocytes (monocytes and macrophages) (25), and speci cally in tumor-associated macrophages (TAMs) (27). Here, we propose that TRB and LUR promote a proin ammatory M1-like polarization in hMφ-R that retain viability, which could explain additional antitumor activities of these compounds, directly modulating the immune response.…”

“…TRB and LUR are known to modulate the immune response within the tumor microenvironment by speci cally targeting mononuclear phagocytes (24)(25)(26). Previously, we characterized the biological response of these drugs in human macrophages (hMφ) (27).…”

Strategies to overcome myeloid cell induced immune suppression in the tumor microenvironment

“…It has been shown to selectively reduce TAMs in tumors without affecting the infiltration of T cells ( 112 ). Treatment with trabectedin also inhibits local differentiation of monocytes into TAMs ( 113 ). Use of trabectedin in multiple preclinical animal tumor models demonstrated depletion of TAMs and reduction of tumor growth, suppression of angiogenesis, and reduced concentrations of IL6, CCL2 and CXCL8 ( 114 ).…”

From seaside to bedside: Current evidence and future perspectives in the treatment of breast cancer using marine compounds

“…Trabectedin and its synthetized analogue lurbinectedin are two innovative anticancer alkaloids isolated from extracts of the Caribbean tunicate Ecteinascidia Turbinate ( Figure 3 ). The two compounds are structurally and functionally related; they share the same pentacyclic skeleton and differ in the so-called ring C which confers specific pharmacokinetic and pharmacodynamic features ( Allavena et al, 2022 ). For instance, lurbinectedin has a three-fold higher MTD and a four-fold lower volume of distribution than those of trabectedin, thus allowing higher dose-intensities without a meaningful increase in toxicities ( Takahashi et al, 2016 ).…”