Sanders Kiah L, Fox Barbara A, Bzik David J
Department of Microbiology and Immunology, Geisel School of Medicine at Dartmouth, Lebanon, New Hampshire.
Cancer Immunol Res. 2015 Aug;3(8):891-901. doi: 10.1158/2326-6066.CIR-14-0235. Epub 2015 Mar 24.
Suppressive myeloid cells represent a significant barrier to the generation of productive antitumor immune responses to many solid tumors. Eliminating or reprogramming suppressive myeloid cells to abrogate tumor-associated immune suppression is a promising therapeutic approach. We asked whether treatment of established aggressive disseminated pancreatic cancer with the immunotherapeutic attenuated Toxoplasma gondii vaccine strain CPS would trigger tumor-associated myeloid cells to generate therapeutic antitumor immune responses. CPS treatment significantly decreased tumor-associated macrophages and markedly increased dendritic cell infiltration of the pancreatic tumor microenvironment. Tumor-resident macrophages and dendritic cells, particularly cells actively invaded by CPS, increased expression of costimulatory molecules CD80 and CD86 and concomitantly boosted their production of IL12. CPS treatment increased CD4(+) and CD8(+) T-cell infiltration into the tumor microenvironment, activated tumor-resident T cells, and increased IFNγ production by T-cell populations. CPS treatment provided a significant therapeutic benefit in pancreatic tumor-bearing mice. This therapeutic benefit depended on IL12 and IFNγ production, MyD88 signaling, and CD8(+) T-cell populations. Although CD4(+) T cells exhibited activated effector phenotypes and produced IFNγ, CD4(+) T cells as well as natural killer cells were not required for the therapeutic benefit. In addition, CD8(+) T cells isolated from CPS-treated tumor-bearing mice produced IFNγ after re-exposure to pancreatic tumor antigen, suggesting this immunotherapeutic treatment stimulated tumor cell antigen-specific CD8(+) T-cell responses. This work highlights the potency and immunotherapeutic efficacy of CPS treatment and demonstrates the significance of targeting tumor-associated myeloid cells as a mechanism to stimulate more effective immunity to pancreatic cancer.
抑制性髓系细胞是对许多实体瘤产生有效的抗肿瘤免疫反应的一个重大障碍。消除或重编程抑制性髓系细胞以消除肿瘤相关的免疫抑制是一种很有前景的治疗方法。我们研究了用免疫治疗性减毒弓形虫疫苗株CPS治疗已建立的侵袭性播散性胰腺癌是否会触发肿瘤相关的髓系细胞产生治疗性抗肿瘤免疫反应。CPS治疗显著减少了肿瘤相关巨噬细胞，并显著增加了胰腺肿瘤微环境中树突状细胞的浸润。肿瘤驻留巨噬细胞和树突状细胞，特别是被CPS主动侵袭的细胞，共刺激分子CD80和CD86的表达增加，并同时提高了它们的IL12产生。CPS治疗增加了CD4(+)和CD8(+) T细胞向肿瘤微环境的浸润，激活了肿瘤驻留T细胞，并增加了T细胞群体的IFNγ产生。CPS治疗在荷胰腺肿瘤小鼠中提供了显著的治疗益处。这种治疗益处依赖于IL12和IFNγ的产生、MyD88信号传导以及CD8(+) T细胞群体。虽然CD4(+) T细胞表现出活化的效应表型并产生IFNγ，但治疗益处并不需要CD4(+) T细胞以及自然杀伤细胞。此外，从接受CPS治疗的荷肿瘤小鼠中分离出的CD8(+) T细胞在再次接触胰腺肿瘤抗原后产生IFNγ，这表明这种免疫治疗刺激了肿瘤细胞抗原特异性CD8(+) T细胞反应。这项工作突出了CPS治疗的效力和免疫治疗效果，并证明了将肿瘤相关髓系细胞作为刺激对胰腺癌产生更有效免疫的一种机制的重要性。
