MerTK-mediated efferocytosis promotes immune tolerance and tumor progression in osteosarcoma through enhancing M2 polarization and PD-L1 expression

Abstract

The poor progress of immunotherapy on osteosarcoma patients requires deeper delineation of immune tolerance mechanisms in the osteosarcoma microenvironment and a new therapeutic strategy. Clearance of apoptotic cells by phagocytes, a process termed “efferocytosis,” is ubiquitous in tumors and mediates the suppression of innate immune inflammatory response. Considering the massive infiltrated macrophages in osteosarcoma, efferocytosis probably serves as a potential target, but is rarely studied in osteosarcoma. Here, we verified M2 polarization and PD-L1 expression of macrophages following efferocytosis. Pharmacological inhibition and genetic knockdown were used to explore the underlying pathway. Moreover, tumor progression and immune landscape were evaluated following inhibition of efferocytosis in osteosarcoma model. Our study indicated that efferocytosis promoted PD-L1 expression and M2 polarization of macrophages. Ëfferocytosis was mediated by MerTK receptor in osteosarcoma and regulated the phenotypes of macrophages through the p38/STAT3 pathway. By establishing the murine osteosarcoma model, we emphasized that inhibition of MerTK suppressed tumor growth and enhanced the T cell cytotoxic function by increasing the infiltration of CD8 + T cells and decreasing their exhaustion. Our findings demonstrate that MerTK-mediated efferocytosis promotes osteosarcoma progression by enhancing M2 polarization of macrophages and PD-L1-induced immune tolerance, which were regulated through the p38/STAT3 pathway.

Tissue-specific modifier alleles determineMertkloss-of-function traits

“…3A, B ). Consistent with previous reports of MERTK blockade enhancing anti-tumor response 10,12,13,21-27 , 100% of Mertk -/- V1 mice remained tumor free, compared to 0% of B6 WT control mice ( Fig. 3B ).…”

“…An important, newly discovered role of MERTK is as an innate immune checkpoint in cancer 10,12,13,21-27 . Mertk -/- V1 mice were used to demonstrate improved anti-tumor immune response against MMTV-PyVmT, B16:F10 and MC38 tumor models 10 .…”

“…Mertk targeting in 129P2 ES cells results in a robust anti-tumor response against immune checkpoint inhibitor (ICI)-refractory YUMM1.7 melanoma and GL261 brain tumor, but this effect is not phenocopied in Mertk -/-V2 or Mertk -/-V3 mice An important, newly discovered role of MERTK is as an innate immune checkpoint in cancer 10,12,13,[21][22][23][24][25][26][27] . Mertk -/-V1 mice were used to demonstrate improved anti-tumor immune response against MMTV-PyVmT, B16:F10 and MC38 tumor models 10 .…”

“…Nevertheless, loss of MERTK is also proposed to hinder macrophage-dependent phagocytosis of dead or dying cancer cells (efferocytosis). This deficiency in macrophage-mediated disposal of tumor cells, in turn, is postulated to improve availability of tumor antigens for proficient presentation on dendritic cells (DCs), and/or render the tumor microenvironment pro-inflammatory and less immunosuppressive 11,12,21 . Paradoxical to this view, macrophages from Mertk -/- V1 , Mertk -/- V2 or Mertk -/- V3 mice all displayed significant deficit in efferocytosis.…”

Efferocytosis and Its Role in Inflammatory Disorders

“…It has been demonstrated that efferocytosis not only facilitates the proliferation, invasion, metastasis, and angiogenesis of tumor cells, but also affects the drug resistance to anti-cancer treatments (Birge et al, 2016;Barkal et al, 2018;Barkal et al, 2019;Tajbakhsh et al, 2021). Recently, Lin et al reported that MERTK-mediated efferocytosis promotes immune tolerance and tumor progression in osteosarcoma through enhancing M2 polarization and programmed death ligand-1 expression (Lin et al, 2022). Furthermore, an excellent study revealed that blockade of phagocytic receptor MERTK on tumorassociated macrophages augmented tumor immunogenicity and potentiated anti-tumor immunity via inducing tumor-cGas and host-STING-dependent type I interferon response (Zhou et al, 2020).…”