Antitumor Immunity Induced after α Irradiation

Abstract

Radioimmunotherapy (RIT) is a therapeutic modality that allows delivering of ionizing radiation directly to targeted cancer cells. Conventional RIT uses β-emitting radioisotopes, but recently, a growing interest has emerged for the clinical development of α particles. α emitters are ideal for killing isolated or small clusters of tumor cells, thanks to their specific characteristics (high linear energy transfer and short path in the tissue), and their effect is less dependent on dose rate, tissue oxygenation, or cell cycle status than γ and X rays. Several studies have been performed to describe α emitter radiobiology and cell death mechanisms induced after α irradiation. But so far, no investigation has been undertaken to analyze the impact of α particles on the immune system, when several studies have shown that external irradiation, using γ and X rays, can foster an antitumor immune response. Therefore, we decided to evaluate the immunogenicity of murine adenocarcinoma MC-38 after bismuth-213 ((213)Bi) irradiation using a vaccination approach. In vivo studies performed in immunocompetent C57Bl/6 mice induced a protective antitumor response that is mediated by tumor-specific T cells. The molecular mechanisms potentially involved in the activation of adaptative immunity were also investigated by in vitro studies. We observed that (213)Bi-treated MC-38 cells release "danger signals" and activate dendritic cells. Our results demonstrate that α irradiation can stimulate adaptive immunity, elicits an efficient antitumor protection, and therefore is an immunogenic cell death inducer, which provides an attractive complement to its direct cytolytic effect on tumor cells.

Consensus guidelines for the detection of immunogenic cell death

“…22 It turned out that the unsuspected ability of doxorubicin (an anthracycline employed for the treatment of various carcinomas) to trigger ICD as a standalone intervention, hence converting dying cancer cells into a vaccine that is efficient in the absence of adjuvants, is shared by a relatively restricted set of lethal triggers. [28][29][30][31][32][33] These include, but perhaps are not limited to, mitoxantrone and epirubicin (2 other anthracyclines currently used in the clinic), [34][35][36][37] bleomycin (a glycopeptide antibiotic endowed with antineoplastic properties), 38 oxaliplatin (a platinum derivative generally employed against colorectal carcinoma), [39][40][41][42] cyclophosphamide (an alkylating agent approved for the treatment of neoplastic and autoimmune conditions), [43][44][45][46][47][48] etoposide (a topoisomerase inhibitor currently used for the treatment of several neoplasms) combined with the chemical inhibitor of glycolysis 2-deoxyglucose, 49,50 patupilone (a microtubular inhibitor that has not yet been approved for use in humans), [51][52][53] septacidin (an antifungal antibiotic produced by Streptomyces fibriatus) 54,55 specific forms of radiation therapy, 34,[56][57][58][59][60][61][62][63][64] photodynamic therapy (a clinically approved antican...…”

α-Emitters for Radiotherapy: From Basic Radiochemistry to Clinical Studies—Part 1

“…The mechanism of this effect is not fully understood but is hypothesized to result from extracellular reactive oxygenated species, chromosomal instabilities, or other abnormalities. Finally, the abscopal effect, resulting from a radiation-induced immune response, is characterized by a therapeutic response in remote lesions (9). Importantly, compared with b-particle radiotherapy, which relies mainly on the formation of reactive oxygen species, the cell-killing efficiency of a-particles was shown to be independent of cellular oxygenation (10).…”

Radio-immunothérapie alpha

“…À la surface des cellules tumorales, les molécules qui peuvent être modifiées par de telles doses de rayonnements ionisants correspondent aux antigènes associés aux tumeurs, aux molécules SYNTHÈSE REVUES DAMP (danger associated molecular pattern) comme la protéine de choc thermique Hsp70 et HMGB1 (highmobility group box 1), une protéine constitutive de la chromatine qui joue un rôle dans l'inflammation, comme cela se produit dans les mécanismes de mort immunogène [42,43]. Ces DAMP permettent, entre autre, l'activation des cellules dendritiques pour le développement de l'immunité antitumorale dépendante des cellules T, ainsi que la mise en place d'une mémoire immunitaire [41]. Cette étude démontre de nouvelles propriétés sur le mécanisme d'action des particules α ainsi que de la RITα.…”

“…Notre équipe a étudié les effets du bismuth-213 sur l'immunogénicité d'un modèle d'adénocarcinome colique murin (MC-38), dans la souris immunocompétente C57BL/6 [41]. L'irradiation α de cellules tumorales par le bismuth-213 permet, dans notre modèle, l'induction d'une immunité antitumorale durable et spécifique.…”