Department of Immunohematology and Blood Transfusion, section Tumorimmunology, Leiden University Medical Center, Leiden, The Netherlands.
Leiden Institute of Chemistry, Leiden University, Leiden, The Netherlands.
J Immunother Cancer. 2018 Dec 12;6(1):146. doi: 10.1186/s40425-018-0455-2.
Ligands for the Toll-like receptor (TLR) family can induce activation of cells of the innate immune system and are widely studied for their potential to enhance adaptive immunity. Conjugation of TLR2-ligand Pam3CSK4 to synthetic long peptides (SLPs) was shown to strongly enhance the induction of antitumor immunity. To further improve cancer vaccination, we have previously shown that the novel TLR2-L Amplivant (AV), a modified Pam3CSK4, potentiates the maturation effects on murine DCs. In the current study, we further assessed the immunological properties of AV.
Naïve mice were vaccinated with a conjugate of either Pam3CSK4 or AV and an SLP to assess specific T cell priming efficiency in vivo. The potency of AV and Pam3CSK4, either as free compounds or conjugated to different SLPs, to mature murine DCs was compared by stimulating murine dendritic cells overnight followed by ELISA and flow cytometry analysis. Murine tumor experiments were carried out by vaccinating mice carrying established HPV16 E6 and E7-expressing tumors and subsequently analyzing myeloid and lymphoid cells infiltrating the tumor microenvironment. Furthermore, tumor outgrowth after vaccination was monitored to enable comparison of the efficiency to induce antitumor immunity by Pam3CSK-SLP and AV-SLP conjugates. To enhance therapeutic efficacy, AV-SLP conjugate vaccination was combined with ablative therapies to assess whether synergism between such therapies would occur.
SLPs conjugated to AV induce stronger DC maturation, in vivo T cell priming and antitumor immunity compared to conjugates with Pam3CSK4. Interestingly, AV-SLP conjugates modulate the macrophage populations in the tumor microenvironment, correlating with a therapeutic effect in an aggressive murine tumor model. The potency of AV-SLP conjugates in cancer vaccination operates optimally in combination with chemotherapy or photodynamic therapy.
These data allow further optimization of vaccination-based immunotherapy of cancer by use of the improved TLR2-ligand Amplivant.
Toll 样受体（TLR）家族的配体可诱导固有免疫系统细胞的激活，并因其增强适应性免疫的潜力而受到广泛研究。已证明 TLR2 配体 Pam3CSK4 与合成长肽（SLP）缀合可强烈增强抗肿瘤免疫的诱导。为了进一步改善癌症疫苗接种，我们之前已经表明，新型 TLR2-L Amplivant（AV），一种改良的 Pam3CSK4，可增强对小鼠 DC 的成熟作用。在本研究中，我们进一步评估了 AV 的免疫学特性。
用 Pam3CSK4 或 AV 与 SLP 的缀合物对幼稚小鼠进行疫苗接种，以评估体内特定 T 细胞的初始效率。通过 overnight 刺激小鼠树突状细胞，然后通过 ELISA 和流式细胞术分析，比较 AV 和 Pam3CSK4 作为游离化合物或与不同 SLP 缀合的成熟小鼠 DC 的效力。通过接种携带已建立的 HPV16 E6 和 E7 表达肿瘤的小鼠，并随后分析浸润肿瘤微环境的髓样和淋巴样细胞，进行小鼠肿瘤实验。此外，监测接种后的肿瘤生长情况，以比较 Pam3CSK-SLP 和 AV-SLP 缀合物诱导抗肿瘤免疫的效率。为了增强治疗效果，将 AV-SLP 缀合物疫苗接种与消融治疗相结合，以评估这些治疗方法之间是否会发生协同作用。
与 Pam3CSK4 缀合的 SLP 相比，AV 缀合的 SLP 可诱导更强的 DC 成熟、体内 T 细胞初始和抗肿瘤免疫。有趣的是，AV-SLP 缀合物可调节肿瘤微环境中的巨噬细胞群体，与侵袭性小鼠肿瘤模型中的治疗效果相关。AV-SLP 缀合物在癌症疫苗接种中的效力在与化学疗法或光动力疗法联合使用时最佳。
这些数据允许通过使用改良的 TLR2 配体 Amplivant 进一步优化基于疫苗接种的癌症免疫疗法。
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