Croci Stefania, Nanni Patrizia, Palladini Arianna, Nicoletti Giordano, Grosso Valentina, Benegiamo Giorgia, Landuzzi Lorena, Lamolinara Alessia, Ianzano Marianna L, Ranieri Dario, Dall'Ora Massimiliano, Iezzi Manuela, De Giovanni Carla, Lollini Pier-Luigi
Laboratory of Immunology and Biology of Metastases, Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, Viale Filopanti 22, Bologna, 40126, Italy.
Present address: Unit of Clinical Immunology, Allergy and Advanced Biotechnologies, Arcispedale Santa Maria Nuova-IRCCS, Viale Risorgimento 80, Reggio Emilia, 42123, Italy.
Breast Cancer Res. 2015 May 22;17(1):70. doi: 10.1186/s13058-015-0588-x.
We previously demonstrated that HER2/neu-driven mammary carcinogenesis can be prevented by an interleukin-12 (IL-12)-adjuvanted allogeneic HER2/neu-expressing cell vaccine. Since IL-12 can induce the release of interleukin-15 (IL-15), in the present study we investigated the role played by IL-15 in HER2/neu driven mammary carcinogenesis and in its immunoprevention.
HER2/neu transgenic mice with homozygous knockout of IL-15 (here referred to as IL15KO/NeuT mice) were compared to IL-15 wild-type HER2/neu transgenic mice (NeuT) regarding mammary carcinogenesis, profile of peripheral blood lymphocytes and splenocytes and humoral and cellular responses induced by the vaccine.
IL15KO/NeuT mice showed a significantly earlier mammary cancer onset than NeuT mice, with median latency times of 16 and 20 weeks respectively, suggesting a role for IL-15 in cancer immunosurveillance. Natural killer (NK) and CD8+ lymphocytes were significantly lower in IL15KO/NeuT mice compared to mice with wild-type IL-15. The IL-12-adjuvanted allogeneic HER2/neu-expressing cell vaccine was still able to delay mammary cancer onset but efficacy in IL-15-lacking mice vanished earlier: all vaccinated IL15KO/NeuT mice developed tumors within 80 weeks of age (median latency of 53 weeks), whereas more than 70 % of vaccinated NeuT mice remained tumor-free up to 80 weeks of age. Vaccinated IL15KO/NeuT mice showed less necrotic tumors with fewer CD3+ lymphocyes and lacked perforin-positive infiltrating cells compared to NeuT mice. Concerning the anti-vaccine antibody response, antibody titer was unaffected by the lack of IL-15, but less antibodies of IgM and IgG1 isotypes were found in IL15KO/NeuT mice. A lower induction by vaccine of systemic interferon-gamma (IFN-γ) and interleukin-5 (IL-5) was also observed in IL15KO/NeuT mice when compared to NeuT mice. Finally, we found a lower level of CD8+ memory cells in the peripheral blood of vaccinated IL15KO/NeuT mice compared to NeuT mice.
We demonstrated that IL-15 has a role in mammary cancer immunosurveillance and that IL-15-regulated NK and CD8+ memory cells play a role in long-lasting immunoprevention, further supporting the potential use of IL-15 as adjuvant in immunological strategies against tumors.
我们之前证明，白细胞介素-12（IL-12）佐剂化的同种异体表达HER2/neu的细胞疫苗可预防HER2/neu驱动的乳腺癌发生。由于IL-12可诱导白细胞介素-15（IL-15）的释放，在本研究中，我们调查了IL-15在HER2/neu驱动的乳腺癌发生及其免疫预防中所起的作用。
将IL-15纯合敲除的HER2/neu转基因小鼠（以下称为IL15KO/NeuT小鼠）与IL-15野生型HER2/neu转基因小鼠（NeuT小鼠）在乳腺癌发生、外周血淋巴细胞和脾细胞谱以及疫苗诱导的体液和细胞反应方面进行比较。
IL15KO/NeuT小鼠的乳腺癌发病明显早于NeuT小鼠，中位潜伏期分别为16周和20周，表明IL-15在癌症免疫监视中发挥作用。与野生型IL-15小鼠相比，IL15KO/NeuT小鼠的自然杀伤（NK）细胞和CD8+淋巴细胞明显减少。IL-12佐剂化的同种异体表达HER2/neu的细胞疫苗仍能延迟乳腺癌发病，但在缺乏IL-15的小鼠中疗效消失得更早：所有接种疫苗的IL15KO/NeuT小鼠在80周龄内都出现了肿瘤（中位潜伏期为53周），而超过70%接种疫苗的NeuT小鼠在80周龄时仍无肿瘤。与NeuT小鼠相比，接种疫苗的IL15KO/NeuT小鼠的肿瘤坏死较少，CD3+淋巴细胞较少，且缺乏穿孔素阳性浸润细胞。关于抗疫苗抗体反应，抗体滴度不受IL-15缺乏的影响，但在IL15KO/NeuT小鼠中发现的IgM和IgG1同种型抗体较少。与NeuT小鼠相比，IL15KO/NeuT小鼠接种疫苗后全身干扰素-γ（IFN-γ）和白细胞介素-5（IL-5）的诱导水平也较低。最后，我们发现与NeuT小鼠相比，接种疫苗的IL15KO/NeuT小鼠外周血中CD8+记忆细胞水平较低。
我们证明IL-15在乳腺癌免疫监视中发挥作用，且IL-15调节的NK细胞和CD8+记忆细胞在长期免疫预防中发挥作用，进一步支持了将IL-15用作抗肿瘤免疫策略佐剂的潜力。
