Rossetti Renata A M, da Silva-Junior Ildefonso A, Rodríguez Gretel R, Alvarez Karla L F, Stone Simone C, Cipelli Marcella, Silveira Caio R F, Beldi Mariana Carmezim, Mota Giana R, Margarido Paulo F R, Baracat Edmund C, Uno Miyuki, Villa Luisa L, Carvalho Jesus P, Yokochi Kaori, Rosa Maria Beatriz S F, Lorenzi Noely P, Lepique Ana Paula
Department of Immunology, Instituto de Ciências Biomédicas, Universidade de Sao Paulo, São Paulo, Brazil.
Department of Radiology and Oncology, Faculdade de Medicina da Universidade de Sao Paulo, Instituto do Câncer do Estado de São Paulo, São Paulo, Brazil.
Front Oncol. 2020 Nov 19;10:587132. doi: 10.3389/fonc.2020.587132. eCollection 2020.
Cervical cancer, which main etiologic factor is Human Papillomavirus (HPV) infection, continues to be a burden for public health systems in developing countries. Our laboratory has been working with the hypothesis that signals generated in the tumor microenvironment can modulate local and systemic immune responses. In this context, it would be reasonable to think that tumors create pro-tumoral bias in immune cells, even before they are recruited to the tumor microenvironment. To understand if and how signaling started in the tumor microenvironment can influence cells within the tumor and systemically, we investigated the expression of key proteins in signaling pathways important for cell proliferation, viability, immune responses and tolerance. Besides, we used detection of specific phosphorylated residues, which are indicative of activation for Akt, CREB, p65 NFκB, and STAT3. Our findings included the observation of a significant STAT3 expression increase and p65 NFκB decrease in circulating leukocytes in correlation with lesion grade. In light of those observations, we started investigating the result of the inhibition of STAT3 in a tumor experimental model. STAT3 inhibition impaired tumor growth, increased anti-tumor T cell responses and decreased the accumulation of myeloid cells in the spleen. The concomitant inhibition of NFκB partially reversed these effects. This study indicates that STAT3 and NFκB are involved in immunomodulatory tumor effects and STAT3 inhibition could be considered as therapy for patients with cervical cancer.
宫颈癌的主要病因是人类乳头瘤病毒（HPV）感染，它仍然是发展中国家公共卫生系统的一大负担。我们实验室一直基于这样的假设开展研究，即肿瘤微环境中产生的信号可以调节局部和全身免疫反应。在这种情况下，有理由认为肿瘤甚至在免疫细胞被招募到肿瘤微环境之前，就在免疫细胞中产生了促肿瘤偏向。为了了解肿瘤微环境中启动的信号是否以及如何影响肿瘤内和全身的细胞，我们研究了对细胞增殖、活力、免疫反应和耐受性重要的信号通路中关键蛋白的表达。此外，我们检测了特定的磷酸化残基，这些残基表明Akt、CREB、p65 NFκB和STAT3被激活。我们的研究结果包括观察到循环白细胞中STAT3表达显著增加而p65 NFκB表达降低，且与病变分级相关。鉴于这些观察结果，我们开始在肿瘤实验模型中研究抑制STAT3的结果。抑制STAT3会损害肿瘤生长，增加抗肿瘤T细胞反应，并减少脾脏中髓样细胞的积累。同时抑制NFκB会部分逆转这些效应。这项研究表明STAT3和NFκB参与了肿瘤的免疫调节作用，抑制STAT3可被视为宫颈癌患者的一种治疗方法。
