PI3Kgamma Inhibitor Attenuates Immunosuppressive Effect of Poly(l-Glutamic Acid)-Combretastatin A4 Conjugate in Metastatic Breast Cancer.

Vascular disrupting agents (VDAs) have great potential for cancer treatment. Poly(l-glutamic acid)-combretastatin A4 conjugate (PLG-CA4) is a novel class of VDAs. Though it has notable antitumor activity, it can induce host immune responses that promote tumor growth. Here, PLG-CA4 induces the polarization of tumor-associated macrophages (TAMs) toward the M2-like phenotype in 4T1 metastatic breast cancer (Control 30% vs PLG-CA4 53%; p < 0.05). Compared to the monotherapy of PLG-CA4, inhibition of phosphoinositide 3-kinase gamma (PI3Kγ) attenuates the immunosuppressive effect of PLG-CA4 treatment by decreasing the number of M2-like TAMs (2.0 × 10⁴ to 1.5 × 10⁴ per tumor) and potential enhancement of cytotoxic T lymphocyte (3.0 × 10⁴ to 5.7 × 10⁴ per tumor). Importantly, PI3Kγ inhibitor synergizing with PLG-CA4 significantly extends the mean survival time from 52 days in monotherapy-treated mice to 61.8 days. Additionally, the combination of PLG-CA4 and PI3Kγ inhibitor improves the tumor therapeutic effect of NLG919, an inhibitor of immune checkpoint indoleamine 2,3-dioxygenase (IDO). As far as it is known, this is the first demonstrated study that VDAs induce the reshaping of macrophages to the M2-like phenotype. The findings also indicate a potential therapeutic strategy of the combination VDAs with an accurate immune modifier in the tumor to reverse the immune resistance.