Macrophage Regulation of Tumor Responses to Anticancer Therapies: Cancer Cell

+ cytotoxic T cells and possibly reduced their tumoricidal activitynHighlight:taxanes profoundly alter macrophage gene expression in vitro (

  • Javeed A.
  • Ashraf M.
  • Riaz A.
  • Ghafoor A.
  • Afzal S.
  • Mukhtar M.M.
Paclitaxel and immune system.
) but also induce tumor damage and cancer cell death, which may trigger a reparative, “wound healing” response in TAMsnHighlight:TAMs may enhance tumor chemoresistance by providing survival signals to tumor-initiating/cancer stem cells (CSCs)nHighlight:Tumor hypoxia and necrosis dramatically increase after the selective destruction of tumor blood vessels by high-dose antiangiogenic drugs or vascular-disrupting agents (VDAs)nHighlight:TAMs express surface receptors that bind the Fc fragment of antibodies and enable them to engage in Ab-dependent cellular cytotoxicity/phagocytosis (ADCC/ADCP)nHighlight:Trastuzumab, a moAb against the human epidermal growth factor receptor-2 (HER2), not only interrupts HER2 signaling in breast cancer cells, thereby slowing their proliferation rate, but also induces Fcγ receptor (FcγR)-mediated activation of macrophage cytotoxicity (
  • Clynes R.A.
  • Towers T.L.
  • Presta L.G.
  • Ravetch J.V.
Inhibitory Fc receptors modulate in vivo cytotoxicity against tumor targets.
) and priming of antigen-specific CD8+ T cell responses in MMTV-Neu tumorsnHighlight:TAM-mediated immunosuppression is mediated, at least in part, by induction of T cell apoptosis and nitrosylation of T cell receptors via macrophage products, like ARG1, NOS2, and peroxynitritenHighlight:It is possible that incipient tumors, which are likely to be more immunogenic than established lesions, contain higher proportions of M1-like TAMs, which could initiate and/or potentiate adaptive immune responsesnHighlight:increasing data suggest that the efficacy of some forms of immunotherapy may also depend on effective reprogramming of TAMs toward an M1-like phenotypenHighlight:macrophages and DCs express programmed cell death ligand-1 (PDL1, also known as B7-H1), a major negative regulatory ligand that suppresses T cell activation through its receptor-programmed cell death protein 1. The promising therapeutic activity of anti-PDL1 moAbs in patients with advanced cancer (
  • Brahmer J.R.
  • Tykodi S.S.
  • Chow L.Q.
  • Hwu W.J.
  • Topalian S.L.
  • Hwu P.
  • Drake C.G.
  • Camacho L.H.
  • Kauh J.
  • Odunsi K.
  • et al.
Safety and activity of anti-PD-L1 antibody in patients with advanced cancer.
) will no doubt prompt further studies of the possible inhibition of PDL1 expression on TAMs to improve the efficacy of chemo- or antiangiogenic therapies.nHighlight:Various preclinical studies have also highlighted ways to reprogram TAMs from an M2 to an M1-like phenotype in tumors. These include the use of histidine-rich glycoprotein (HRG), which induces macrophage downregulation of PlGF, promotes the normalization of blood vessels, and increases delivery and efficacy of chemotherapy in mouse tumor models (
  • Rolny C.
  • Mazzone M.
  • Tugues S.
  • Laoui D.
  • Johansson I.
  • Coulon C.
  • Squadrito M.L.
  • Segura I.
  • Li X.
  • Knevels E.
  • et al.
HRG inhibits tumor growth and metastasis by inducing macrophage polarization and vessel normalization through downregulation of PlGF.
; Figure 1A). Other strategies to reprogram TAMs include blockade of nuclear factor-kB signaling (
  • Hagemann T.
  • Lawrence T.
  • McNeish I.
  • Charles K.A.
  • Kulbe H.
  • Thompson R.G.
  • Robinson S.C.
  • Balkwill F.R.
“Re-educating” tumor-associated macrophages by targeting NF-kappaB.
) or their exposure to anti-IL-10R antibodies combined with the TLR9 ligand CpGn]]>

About Dr. Nathan Goodyear
About Dr. Nathan Goodyear

Dr. Nathan Goodyear, a medical doctor with years of experience in the field of integrative cancer care, has announced the launch of an online training program. This program, available on his new website, will provide individuals with access to video trainings led by Dr. Goodyear himself, covering a range of topics related to integrative cancer care. These trainings will include information on the latest research and techniques in the field, as well as guidance on how to incorporate these approaches into a patient’s overall cancer treatment plan. With this online program, Dr. Goodyear hopes to make his expertise and knowledge more widely accessible, and help more people understand the benefits of integrative cancer care.


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