Immunostimulating liposomes targeting M2 macrophage to eradicate cancer
Mr. Kunal Pednekar (PhD fellow sponsored by the PRC) - University of Twente/the Netherlands
The adaptive immune system, cytotoxic T-cells have an ability to recognize and destroy cancer cells. However, tumor-associated macrophages (TAMs) within the tumor microenvironment induce immunosuppression by secreting various cytokines1), which in turn inhibit immune cells to attack cancer cells. Macrophages generally represent two phenotypes, namely M1 (as anti-tumoral) and M2 (as pro-tumoral). TAMs mainly represent M2 type macrophages which are highly pro-tumorigenic. Transformation of M2 into M1 type is of high interest, as this can revert TAM-induced “immunosuppressive microenvironment” into “immunostimulating microenvironment”. Earlier with the support of the Phospholipid Research Center, we have developed carboxylated phospholipid-based liposomes system that can specifically target M2 macrophages (previous project: Design of well-defined liposomes to target tumor-associated M2 macrophages). We demonstrated that carboxylated liposomes can be used to deliver different drugs such as zoledronic acid and MTP-PE to M2 macrophages. Interestingly, MTP-PE-containing carboxylated liposomes converted M2 macrophages into M1 type in vitro and reduced the tumor growth by 70% in orthotopic breast tumor model in vivo.
In this project, to achieve the complete eradication of tumors which is our end goal, we have set two objectives: 1) target immunostimulating agents2) together with MTP-PE to achieve complete and efficient transformation of M2 into M1 type; and 2) combine immunostimulating liposomes with immunotherapy to achieve a synergistic effect for complete eradication of cancer. These formulations will be extensively examined in orthotopic breast tumor and melanoma models in vivo to examine their efficacy to inhibit tumor progression as well as metastasis. Altogether, this project will exploit the carboxylated liposome technology to stimulate the anti-tumor immunity by delivering immunostimulating agents to M2 macrophages and eradicate tumor completely.
Benefit for the community
Cancer is the second leading cause of death world-wide and leads to about 9.6 million deaths every year. Cancer makes a huge negative impact to our society both at health and socio-economic levels. Despite having more than 150 FDA-approved chemotherapies and targeted therapies for cancer, treatment of cancer remains a large challenge in the clinic. Immunotherapies are considered the future medicine to cure cancer. However, the success of the treatment is still poor. Increasing evidence show that the tumor microenvironment around tumor cells protect them from the attack of the therapies and immune system.
TAMs are one of the most crucial cell types which contribute to the tumor initiation, migration, and protection from immunotherapy. With previous research funded by the Phospholipid Research Center, we have shown that inhibition of TAMs using our novel liposomal platform could retard the tumor growth in the breast tumor model. Now, we want to develop our technology to enhance the effectivity of immunotherapy, as proposed in this project. A patent has been filed, which will pave a way to bring this technology to clinic. Success of this project will develop new product(s) against cancer which can help reducing the health burden of our society by enhancing the survival rate in cancer patients. Moreover, the new scientific knowledge will also benefit other scientific communities including the phospholipid research, nanomedicine and oncology.