Non-homogenous intratumor ionizing radiation doses synergize with PD1 and CXCR2 blockade

Paul Bergeron, Morgane Dos Santos, Lisa Sitterle, Georges Tarlet, Jeremy Lavigne, Winchygn Liu, Marine Gerbé de Thoré, Céline Clémenson, Lydia Meziani, Cathyanne Schott, Giulia Mazzaschi, Kevin Berthelot, Mohamed Amine Benadjaoud, Fabien Milliat, Eric Deutsch and Michele Mondini ()
Additional contact information
Paul Bergeron: Université Paris-Saclay
Morgane Dos Santos: Institut de Radioprotection et de Sûreté Nucléaire (IRSN), PSE-SANTE/SERAMED/LRAcc
Lisa Sitterle: Université Paris-Saclay
Georges Tarlet: Institut de Radioprotection et de Sûreté Nucléaire (IRSN), PSE-SANTE/SERAMED/LRMed
Jeremy Lavigne: Institut de Radioprotection et de Sûreté Nucléaire (IRSN), PSE-SANTE/SERAMED/LRMed
Winchygn Liu: Université Paris-Saclay
Marine Gerbé de Thoré: Université Paris-Saclay
Céline Clémenson: Université Paris-Saclay
Lydia Meziani: Université Paris-Saclay
Cathyanne Schott: Université Paris-Saclay
Giulia Mazzaschi: Université Paris-Saclay
Kevin Berthelot: Université Paris-Saclay
Mohamed Amine Benadjaoud: Institut de Radioprotection et de Sûreté Nucléaire (IRSN), PSE-SANTE/SERAMED
Fabien Milliat: Institut de Radioprotection et de Sûreté Nucléaire (IRSN), PSE-SANTE/SERAMED/LRMed
Eric Deutsch: Université Paris-Saclay
Michele Mondini: Université Paris-Saclay

Nature Communications, 2024, vol. 15, issue 1, 1-19

Abstract: Abstract The efficacy and side effects of radiotherapy (RT) depend on parameters like dose and the volume of irradiated tissue. RT induces modulations of the tumor immune microenvironment (TIME) that are dependent on the dose. Low dose RT (LDRT, i.e., single doses of 0.5–2 Gy) has been shown to promote immune infiltration into the tumor. Here we hypothesize that partial tumor irradiation combining the immunostimulatory/non-lethal properties of LDRT with cell killing/shrinkage properties of high dose RT (HDRT) within the same tumor mass could enhance anti-tumor responses when combined with immunomodulators. In models of colorectal and breast cancer in immunocompetent female mice, partial irradiation (PI) with millimetric precision to deliver LDRT (2 Gy) and HDRT (16 Gy) within the same tumor induces substantial tumor control when combined with anti-PD1. Using flow cytometry, cytokine profiling and single-cell RNA sequencing, we identify a crosstalk between the TIME of the differentially irradiated tumor volumes. PI reshapes tumor-infiltrating CD8+ T cells into more cytotoxic and interferon-activated phenotypes but also increases the infiltration of pro-tumor neutrophils driven by CXCR2. The combination of the CXCR2 antagonist SB225002 with PD1 blockade and PI improves tumor control and mouse survival. Our results suggest a strategy to reduce RT toxicity and improve the therapeutic index of RT and immune checkpoint combinations.

Date: 2024
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DOI: 10.1038/s41467-024-53015-9

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