Buqué Aitziber, Bloy Norma, Petroni Giulia, Jiménez-Cortegana Carlos, Sato Ai, Iribarren Cristina, Yamazaki Takahiro, Galassi Claudia, Hensler Michal, Bhinder Bhavneet, Guarracino Andrea, Rippon Brady, Beltran-Visiedo Manuel, Soler-Agesta Ruth, Pannellini Tania, Fucikova Jitka, Demaria Sandra, Zhou Xi Kathy, Elemento Olivier, Formenti Silvia C, Galluzzi Lorenzo
Department of Radiation Oncology, Weill Cornell Medicine, New York, NY 10065, United States.
Cancer Signaling and Microenvironment Program, Fox Chase Cancer Center, Philadephia, PA 19111, United States.
J Natl Cancer Inst. 2025 May 1;117(5):934-947. doi: 10.1093/jnci/djae329.
Hormone receptor-positive (HR+) breast cancer responds poorly to immune checkpoint inhibitors (ICIs). In some settings, radiation therapy (RT) has been shown to mediate immunostimulatory effects and promote ICI sensitivity.
We investigated whether hypofractionated RT may be successfully combined with ICIs in a mouse model of multifocal, metachronous HR+ mammary carcinogenesis. We hypothesized that focal RT targeting the first detectable (primary) tumor combined with ICIs may generate effective immunity, delaying the development of new lesions.
Focal RT in various doses and fractionations limited primary tumor growth, with an optimum for a 20-Gy × 2 regimen (ablative in approximately 90% of mice). The degree of primary disease control, however, did not necessarily correlate with overall survival extension because of changes in the development of new neoplastic lesions contributing to global tumor burden. Adding a PD-1 blocker to focal RT delivered in a 10-Gy × 3, 20-Gy × 2, or 8-Gy × 6 regimen failed to alter overall survival extension enabled by RT alone. Similar results were obtained with a CTLA4 blocker, an IL-1β inhibitor, and a PD-1 blocker plus recombinant FLT3LG when combined with the 10-Gy × 3 regimen.
In this model of HR+ mammary carcinogenesis, RT to the primary tumor ameliorates overall survival (to an extent based on dose and fractionation). Increasing local control through RT alone or RT plus immunotherapy beyond a hitherto undefined threshold, however, does not necessarily inhibit the development of subsequent nonirradiated neoplasms and hence does not necessarily provide extra overall survival benefits.
激素受体阳性（HR+）乳腺癌对免疫检查点抑制剂（ICI）反应不佳。在某些情况下，放射治疗（RT）已被证明可介导免疫刺激作用并提高ICI敏感性。
我们在多灶性、异时性HR+乳腺癌发生的小鼠模型中研究了低分割放疗是否可以成功地与ICI联合使用。我们假设针对第一个可检测到的（原发性）肿瘤进行局部放疗并联合ICI可能产生有效的免疫反应，从而延缓新病灶的发展。
不同剂量和分割的局部放疗可限制原发性肿瘤生长，20 Gy×2方案最为理想（约90%的小鼠肿瘤被消融）。然而，由于新肿瘤病灶的发展变化导致总体肿瘤负担增加，原发性疾病的控制程度不一定与总生存期延长相关。在10 Gy×3、20 Gy×2或8 Gy×6方案的局部放疗中添加PD-1阻断剂并不能改变单纯放疗所带来的总生存期延长。当与10 Gy×3方案联合使用时，CTLA4阻断剂、IL-1β抑制剂以及PD-1阻断剂加重组FLT3LG也得到了类似结果。
在这个HR+乳腺癌发生模型中，对原发性肿瘤进行放疗可改善总生存期（改善程度取决于剂量和分割）。然而，仅通过放疗或放疗加免疫疗法将局部控制提高到一个迄今未明确的阈值以上，并不一定能抑制后续未受照射肿瘤的发展，因此不一定能提供额外的总生存期益处。
