疟疾感染与包括肝癌在内的多种肿瘤的发病率存在显著的负性关联。本实验室前期的研究发现，红内期疟原虫感染可以抑制荷瘤小鼠体内的肿瘤生长，并能延长荷瘤小鼠的存活期，但是往往伴随着疟疾的临床症状。目前对于无症状的红前期疟原虫感染与肿瘤的关系尚未见有研究报导。肝癌组织和细胞表面高度表达红前期疟原虫子孢子借以进入肝细胞的高度琉酰化的硫酸肝素蛋白聚糖，使得疟原虫子孢子很容易侵入肝癌细胞中发育并导致细胞破裂。红前期疟原虫感染能够显著激活机体的非特异性和特异性免疫系统。我们推测：疟原虫子孢子在体内入侵肝癌细胞并在其中发育使之破裂的过程中，可以促进肝癌相关抗原的释放从而激活肿瘤特异性杀伤细胞，并通过调节肿瘤的免疫微环境从而影响肿瘤的生长。为验证这一假说，我们计划在小鼠模型中进行子孢子疟原虫感染治疗肝癌的可行性探索，以及其调节机体抗肿瘤免疫相关机理的研究，为开发一种新型有效的肿瘤生物疗法打下基础。

Malaria plasmodium infection is revealed to be negatively correlated with the incidence and mortality of a variety of tumor types including hepatocellular carcinoma (HCC). Previous studies from our laboratory and others showed suppressed tumor growth and prolonged survival in tumor-implanted mice that had received erythrocytic malaria infection. However, such tumor-suppresive effect of malaria infection is always accompanied by high parasitemia that still endangers the host. Surprisingly there is no experimental data reported about tumor immunotherapy using the asymptomatic pre-erythrocytic stage of malaria infection. HCC cells (HCCs) richly express on their surface highly sulfated heparan sulfate proteoglycans (hsHSPG) , which are usually found on hepatocytes for facilitating the productive invasion of plasmodium sporozoites (SPZ) early during pre-erythrocytic infection. Since HCCs can be easily invaded by SPZ and then broken dead by the release of matured merozoites, considering that both innate and adaptive immune responses are induced during pre-erythrocytic malaria infection, it is reasonable to hypothesize that the invasion by SPZ into HCCs could later enhance the release of tumor-associated and/or specific antigens (Ag) from the destroyed HCCs to stimulate tumor Ag-specific cytolytic T cells, and modulate the anti-tumor immune forces in the HCC microenvironment. To test this, we propose to explore in our established mouse model of HCC the feasibility and mechanism of malaria SPZ infection as a new tool for immunotherapy of HCC.

疟疾感染与包括肝癌在内的多种肿瘤的死亡率存在显著的负性关联。本实验室前期的研究发现，红内期疟原虫感染可以抑制荷瘤小鼠体内的肿瘤生长，并能延长荷瘤小鼠的存活期，但是往往伴随着疟疾的临床症状。目前对于无症状的红前期疟原虫感染与肝癌的关系尚未见有研究报导。肝癌组织和细胞表面高度表达红前期疟原虫子孢子借以进入肝细胞的高度琉酰化的硫酸肝素蛋白聚糖，使得疟原虫子孢子很容易侵入肝癌细胞中发育并导致细胞破裂。红前期疟原虫感染能够显著激活机体的非特异性和特异性免疫系统。我们推测：疟原虫子孢子在体内入侵肝癌细胞并在其中发育使之破裂的过程中，可以促进肝癌相关抗原的释放从而激活肿瘤特异性杀伤细胞，并通过调节肿瘤的免疫微环境从而影响肿瘤的生长。为验证这一假说，我们在小鼠模型中进行子孢子疟原虫感染治疗肝癌的可行性探索，以及其调节机体抗肿瘤免疫相关机理的研究。研究结果显示，鼠伯氏疟原虫能够感染Hepa1-6与HC-04细胞，也能够感染人宫颈癌Hela细胞。携带肝癌抗原GPC3蛋白的疟原虫在免疫小鼠后，小鼠肝脏肿瘤明显受到抑制，其生存率得到了显著提高。这与疟原虫能够激活Th1 CD4+ T细胞，并促进CD8α+ DC细胞成熟及其比例上调密切相关。疟原虫作为肝脏肿瘤抗原的有效表达载体可能为疟原虫免疫疗法治疗肝脏肿瘤病人提供新的方法。本项目为开发一种新型有效的肿瘤生物疗法打下基础。