CXCR4 engagement triggers CD47 internalization and antitumor immunization in a mouse model of mesothelioma

Our plain-English summary of CXCR4 engagement triggers CD47 internalization and antitumor immunization in a mouse model of mesothelioma, by R. Mezzapelle, F. De Marchis, C. Passera, et al (EMBO Molecular Medicine, 2021).

The study

• Authors: R. Mezzapelle, F. De Marchis, C. Passera, M. Leo, F. Brambilla, F. Colombo, M. Casalgrandi, A. Preti, S. Zambrano, P. Castellani, R. Ertassi, M. Silingardi, F. Caprioglio, V. Basso, R. Boldorini, A. Carretta, F. Sanvito, O. Rena, A. Rubartelli, L. Sabatino, A. Mondino, M.P. Crippa, V. Colantuoni, M.E. Bianchi
• Journal: EMBO Molecular Medicine
• Published: 2021;13(6):e12344
• Cited by: 21 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Boosting antitumor immunity has emerged as a powerful strategy in cancer treatment. While releasing T-cell brakes has received most attention, tumor recognition by T cells is a pre-requisite. Radiotherapy and certain cytotoxic drugs induce the release of damage-associated molecular patterns, which promote tumor antigen cross-presentation and T-cell priming. Antibodies against the "do not eat me" signal CD47 cause macrophage phagocytosis of live tumor cells and drive the emergence of antitumor T cells. Here we show that CXCR4 activation, so far associated only with tumor progression and metastasis, also flags tumor cells to immune recognition. Both CXCL12, the natural CXCR4 ligand, and BoxA, a fragment of HMGB1, promote the release of DAMPs and the internalization of CD47, leading to protective antitumor immunity. We designate as Immunogenic Surrender the process by which CXCR4 turns in tumor cells to macrophages, thereby subjecting a rapidly growing tissue to immunological scrutiny. Importantly, while CXCL12 promotes tumor cell proliferation, BoxA reduces it, and might be exploited for the treatment of malignant mesothelioma and a variety of other tumors.

© 2021 The Authors. Published under the terms of the CC BY 4.0 license.

In plain English

This laboratory study in mice and cultured cells tested BoxA, a fragment of HMGB1, in a syngeneic model of malignant mesothelioma (a tumour the authors describe as asbestos-associated); mouse AB1-B/c mesothelioma cells were injected into the peritoneum of BALB/c mice. In a first experiment in 12 mice, fewer mice had detectable lesions as the BoxA dose rose (P = 0.04). In a larger experiment, 15 of 20 BoxA-treated mice versus 4 of 20 controls rejected the tumour (P = 0.0012, Fisher's test), and survival differed (P less than 0.0001); survivors rejected a second challenge. CD8-depleted mice all developed tumours whatever the treatment. In culture, BoxA slowed growth without causing apoptosis, triggered release of damage signals, lowered surface CD47 and raised macrophage engulfment of tumour cells from under 1% to almost 20%. In cells with CXCR4 silenced, BoxA no longer reduced proliferation or depleted surface CD47. CXCL12 produced similar CD47 internalisation. In CT26 colon cancer cells BoxA likewise caused calreticulin exposure, HMGB1 release and CD47 depletion; all CT26 control mice died within 19 days and BoxA-treated mice survived longer, one rejecting a re-challenge.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: experimental animal and cell-culture study using a syngeneic mouse mesothelioma model, plus a mouse colon carcinoma model
• Who was studied: Eight-week-old male BALB/c mice inoculated intraperitoneally with mouse AB1 mesothelioma cells or CT26 colon cancer cells; mouse and human tumour cell lines; human mesothelioma pleural biopsies from patients admitted 2015-2017 in Milan and Novara, Italy
• Exposure: BoxA, a fragment of HMGB1, 800 micrograms intraperitoneally three times a week for 3 weeks (10 injections); also doses of 0, 200, 400 and 800 micrograms in a first experiment; in cells, BoxA 100-800 nM, CXCL12 1-100 nM, mitoxantrone 1 microM as comparator
• Main results:
  • In the first small experiment in 12 mice, the number of mice with detectable tumour lesions fell as the BoxA dose rose
  • Survival of BoxA-treated mesothelioma mice versus PBS controls, 20 mice per group
  • Tumour rejection: 15 of 20 BoxA-treated mice versus 4 of 20 control mice
  • Mice depleted of CD8+ T cells all developed tumours whether given BoxA or PBS
  • In mesothelioma cells, BoxA reduced proliferation but did not trigger apoptosis
  • Engulfment of GFP-positive mesothelioma cells by bone marrow-derived macrophages increased with BoxA dose
  • In mesothelioma cells with CXCR4 stably silenced, BoxA neither reduced proliferation nor depleted surface CD47
  • CXCL12, the natural CXCR4 ligand, at 10 to 30 nM produced effects similar to BoxA in mesothelioma cells
  • In CT26 colon cancer cells, BoxA induced calreticulin exposure, HMGB1 release, UPR activation and surface CD47 depletion without causing cell death
  • In the CT26 colon cancer model, all control mice died within 19 days and BoxA-treated mice survived longer, with one survivor that rejected a re-challenge
• The authors' conclusion: The authors concluded that engaging CXCR4 causes CD47 to be internalised, exposing tumour cells to immune surveillance, and that BoxA, which is not cytotoxic, enhances this without promoting cell growth; they named the process Immunogenic Surrender and suggested it may hold promise for malignant mesothelioma
• Limitations the authors state:
  • The authors state most experiments were too small to test whether data were normally distributed
  • The investigator giving the treatments was not blinded
  • The authors note the survival result in the main mesothelioma experiment was not what they had planned the sample size for

Topics

The National Library of Medicine indexes this study under subjects our site covers: Mesothelioma.

Medical terms in this study, explained in our Lexicon: Mesothelioma, Macrophage, Phagocytosis, Metastasis, High Mobility Group Box 1 (HMGB1).

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