P53 inactivation on MDSC development and tumor progression

描述（由申请人提供）：越来越多的证据表明慢性炎症与肿瘤发生、进展和转移有关。临床和实验结果表明，慢性炎症增强肿瘤抑制基因p53的表达，导致其突变和失活。事实上，在50%的人类癌症中观察到p53突变，并且被认为是癌症的主要原因之一。此外，在维持正常p53基因的肿瘤中，p53突变有时发生在肿瘤微环境（TME）内的癌症相关成纤维细胞（CAF）中，这与转移率增加和预后不良相关。尽管已经充分认识到TME中的免疫失调在肿瘤发生中起着至关重要的作用，但p53失活是否免疫调节TME以及p53失活的免疫后果是否在肿瘤发生中起着不可或缺的作用仍然在很大程度上未被探索。由于我们实验室和其他人最近的研究表明，p53无效宿主的免疫环境偏向于炎症，我们假设构成TME的细胞区室中的p53失活通过促进炎症而有利于肿瘤的建立和进展。事实上，我们的研究表明，接种的B16-F1黑色素瘤在p53基因敲除小鼠中比在WT小鼠中进展得更快，这与淋巴样基质网络的显著扩张和髓源性抑制细胞（MDSC）的积累增加有关，这两者都是由于其促炎细胞因子和趋化因子的高表达而具有免疫抑制作用。在这里，我们建议通过以下具体目标，从机制上阐明p53失活如何增强炎症反应并促进MDSC的发育，从而促进肿瘤进展：（1）确定在缺乏功能性p53的肿瘤微环境中肿瘤-基质相互作用是否由于高度活化的NF-κ B途径而导致淋巴样网状成纤维细胞（FRC）网络的扩增，其产生强烈有利于MDSC发育的细胞因子环境和免疫微环境;（2）检查p53缺失宿主中增强的MDSC发育和肿瘤进展是否由p53失活增强的髓样祖细胞增殖和淋巴样FRC介导的MDSC积累的增强贡献;以及（3）确定成纤维细胞和骨髓前体中的p53失活是否协同增强葡聚糖硫酸钠（DSS）诱导的结肠癌中的慢性炎症和肿瘤发生，而成纤维细胞或MDSC中的p53的靶向恢复是否延迟结肠癌的发展。通过关注p53功能障碍在促进MDSC发育和肿瘤进展中的机制，本申请为肿瘤发生中p53功能障碍/失活的免疫学机制提供了新的见解，并为肿瘤治疗提供了靶向TME中p53通路的新策略。.

DESCRIPTION (provided by applicant): Increasing evidence has linked chronic inflammation to tumor development, progression, and metastases. Clinical and experimental results suggest that chronic inflammation enhances expression of the tumor suppressor p53 leading to its mutations and inactivation. In fact, p53 mutations are observed in 50% of human cancers and are considered to be one of the leading causes of cancer. Moreover, in tumors that maintain normal p53 gene, p53 mutations sometimes occur in cancer-associated fibroblasts (CAFs) within the tumor microenvironment (TME), which correlates with an increased rate of metastases and poor prognosis. Although it is well appreciated that immune dysregulation in the TME plays a crucial role in tumorigenesis, whether p53 inactivation immunomodulates the TME and whether the immunological consequence of p53 inactivation plays an integral role in tumorigenesis are still largely unexplored. Since recent studies by our laboratory and others have shown that the immunological environment in p53null hosts is skewed in favor of inflammation, we hypothesized that p53 inactivation in the cellular compartment constituting the TME favors tumor establishment and progression by promoting inflammation. Indeed, our studies showed that inoculated B16-F1 melanoma progressed more rapidly in p53null mice than that in WT mice, which is associated with a marked expansion of the lymphoid-like stromal network and enhanced accumulation of myeloid-derived suppressor cells (MDSC), both of which are immunosuppressive due to their high expression of proinflammatory cytokines and chemokines. Here, we propose to elucidate mechanistically how p53 inactivation enhances inflammatory responses and promotes the development of MDSCs, thereby tumor progression, through the following specific aims: (1) to determine whether tumor-stroma interaction in the tumor microenvironment lacking functional p53 results in the expansion of the lymphoid-like reticular fibroblastic cell (FRC) network, due to highly activated NF-kB pathway, which creates a cytokine milieu and immunological microenvironment strongly favoring MDSC development; (2) to examine whether the augmented MDSC development and tumor progression in p53null hosts are contributed by p53 inactivation enhanced proliferation of myeloid progenitors and lymphoid-like FRC-mediated enhancement of MDSC accumulation; and (3) to determine whether p53 inactivation in fibroblasts and myeloid precursors synergistically enhances chronic inflammation and tumorigenesis in the dextran sulfate sodium (DSS)-induced colon cancer, whereas targeted restoration of p53 in fibroblast or MDSC delays colon cancer development. By focusing on the mechanisms of p53 dysfunction in promoting MDSC development and tumor progression, this application provides novel insights into the immunological mechanism of p53 dysfunction/inactivation in tumorigenesis and new strategies targeting the p53 pathway in the TME that can be implemented to tumor treatment. .