Inhibition of Mac-1 (CD11b/CD18) enhances tumor response to radiation by reducing myeloid cell recruitment

Abstract

Despite recent advances in radiotherapy, loco-regional failures are still the leading cause of death in many cancer patients. We have previously reported that bone marrow-derived CD11b + myeloid cells are recruited to tumors grown in irradiated tissues, thereby restoring the vasculature and tumor growth. In this study, we examined whether neutralizing CD11b monoclonal antibodies could inhibit the recruitment of myeloid cells into irradiated tumors and inhibit their regrowth. We observed a significant enhancement of antitumor response to radiation in squamous cell carcinoma xenografts in mice when CD11b antibodies are administered systemically. Histological examination of tumors revealed that CD11b antibodies reduced infiltration of myeloid cells expressing S100A8 and matrix metalloproteinase-9. CD11b antibodies further inhibited bone marrow-derived cell adhesion and transmigration to C166 endothelial cell monolayers and chemotactic stimuli, respectively, to levels comparable to those from CD11b knockout or CD18 hypomorphic mice. Given the clinical availability of humanized CD18 antibodies, we tested two murine tumor models in CD18 hypomorphic or CD11b knockout mice and found that tumors were more sensitive to irradiation when grown in CD18 hypomorphic mice but not in CD11b knockout mice. When CD18 hypomorphism was partially rescued by reconstitution with the wild-type bone marrow, the resistance of the tumors to irradiation was restored. Our study thus supports the rationale of using clinically available Mac-1 (CD11b/CD18) antibodies as an adjuvant therapy to radiotherapy. S100A8 | vasculogenesis | radiosensitivity

Immune-mediated mechanisms influencing the efficacy of anticancer therapies

“…Similar results are observed using other strategies to block TAMs, including CSF1R inhibitors in combination with fractionated irradiation in subcutaneous prostate tumors [91] and carrageenan in transplantable models [92]. In B16 melanomas, however, the anti-cancer effect of a single local high radiotherapy dose is not affected by the absence of TAMs [96].Depletion of Ly6G + neutrophils and Ly6C + inflammatory monocytes using Gr1 antibodies has no synergistic effect with radiotherapy in subcutaneous human prostate tumors [89].Conversely, the depletion of neutrophilic MDSCs potentiates the efficacy of radiotherapy on subcutaneous colon cancer cells [97], presumably through the alleviation of T cell suppression. Dendritic cells also play a role in radiosensitivity [58,96,98], but their activation by irradiation varies between transplantable models.…”

“…This result may be largely explained by the contribution of MMP9 by CD11b + cells that drives tumor regrowth through vasculogenesis [88,89]. Similar results are observed using other strategies to block TAMs, including CSF1R inhibitors in combination with fractionated irradiation in subcutaneous prostate tumors [91] and carrageenan in transplantable models [92].…”

“…Depletion of Ly6G + neutrophils and Ly6C + inflammatory monocytes using Gr1 antibodies has no synergistic effect with radiotherapy in subcutaneous human prostate tumors [89].…”

“…Monocytes and macrophages expressing TIE2 -the receptor for Angiopoietins 1 and 2 -are highly receptive to increased hypoxia and CXCL12 levels [90,93,94], and TIE2-expressing monocytes/macrophages 10 have a profound ability to counteract hypoxia through the induction of angiogenesis [95]. As one may predict, neutralizing CXCL12 or blocking its receptor, CXCR4, to prevent TAM accumulation further delays tumor progression when combined with radiotherapy in orthotopic syngeneic and xenograft models of glioblastoma [90], as well as subcutaneous xenografts of lung carcinoma and syngeneic mammary tumors [93].When TAMs are depleted in various subcutaneous transplantable and xenograft models by targeting all CD11b + cells, the inhibitory effects of radiation on tumor growth and angiogenesis are augmented [88,89]. This result may be largely explained by the contribution of MMP9 by CD11b + cells that drives tumor regrowth through vasculogenesis [88,89].…”

Neutrophils in cancer: neutral no more

“…Whereas anti-Ly6G antibody-mediated neutrophil depletion improves the efficacy of radiotherapy in a subcutaneous colon cancer model 193 , antibody-mediated depletion of Gr1 + cells does not alter radiotherapy responses of xenografted prostate cancer cells 194 .…”