Effective antitumor immunity depends on appropriately activating a series of responses in the Cancer-Immunity Cycle (CIC)¹. Firstly, dying cancer cells release tumor-associated antigens (TAAs) that are captured and processed by antigen presenting cells (APCs) such as dendritic cells (DCs). Next, APCs present the antigens to T cells, leading to the priming of effector T cell responses against TAAs. These activated effector T cells infiltrate into tumoral tissues and execute the killing of cancer cells. Lastly, dead cancer cells further release antigens to increase the breadth and depth of the immune responses in the CIC. However, these stepwise events are usually dampened by the immunosuppressive tumor microenvironment (TME), resulting in uncontrollable tumor growth, metastasis, and recurrence^1-5. Dendritic cells are important intermediators for connecting innate and adaptive immunity in the CIC¹. Nevertheless, their functions are usually restrained by the TME by reducing their recruitment, infiltration, and maturation^1-5. Although the adoptive transfer of engineered DCs has provided important safety and immunogenicity data from many clinical trials, their clinical responses are unsatisfactory^2,3,6.

Can we overcome the challenges of closing the CIC using engineered DCs? After literature research, Dr. Yizhou Dong and I thought that an effective treatment should simultaneously induce the release of TAAs and activate DCs in the TME. Given the versatility of lipid nanoparticle (LNP)-mRNA formulations, we proposed a treatment regimen called CATCH via integrating LNP-mRNA formulations and DC therapy. Then, we discussed this idea with Dr. Yuebao Zhang who specialized in chemical synthesis of novel lipid derivatives. After careful consideration of lipid chemistry, Dr. Zhang designed and synthesized a series of sugar alcohol-derived lipids with unique chirality, rigidity, and biodegradability. Meanwhile, we selected CD40 and CD40 ligand (CD40L), a pair of costimulatory molecules, for DC activation^7,8. The interaction between CD40 and CD40L is crucial for DC maturation, which can promote the secretion of proinflammatory cytokines and the upregulation of other costimulatory molecules^7,8. These events play central roles in triggering CD8 T cells to develop cytotoxic and memory responses^7,8. After systematic screening and optimization, we identified two optimal LNP formulations for mRNA delivery. One LNP induced robust immunogenic cell death (ICD) in tumoral tissues, and in the meantime effectively delivered CD40L mRNA into cancer cells. The other LNP showed dramatically higher CD40 mRNA delivery efficiency in bone marrow derived dendritic cells (BMDCs) than the state-of-art delivery technologies.

With the great support of Dr. Shi Du and other lab members, we performed experiments in multiple mouse tumor models. The CATCH treatment resulted in about 50% to 100% complete response rates in multiple subcutaneous (s.c.) tumor models. Moreover, the local treatment enabled the inhibition or elimination of skin and brain tumor metastasis. Importantly, these responder mice were resistant to s.c. rechallenge and showed delayed tumor growth after intracranial (i.c.) rechallenge. Mechanically, the CATCH treatment induced multiple pro-inflammatory cytokines and chemokines in both tumoral tissues and blood. These immune responses contributed to TME reprogramming and systemic immunity, which not only promoted the trafficking and migration of immune cells into tumoral tissues but also facilitated the priming of APCs and effector T cells. The primed T cells elicited their cytotoxicity against cancer cells. As a result, dead cancer cells further release antigens to increase the breadth and depth of the immune responses in the CIC.

Collectively (Fig. 1), CD40L-LNPs in CATCH treatment simultaneously induced ICD and CD40L expression in tumoral tissues, which enabled to activate adoptively transferred CD40-BMDCs, the second component of CATCH regimen. The activation of DCs enhanced their presentation of TAAs and expression of costimulatory molecules, and in the meantime induced multiple cytokines and chemokines in both tumoral tissues and blood. These immune events contributed to reprogramming the TME and systemic immune responses, which promoted the migration of immune cells into tumoral tissues, the priming of effector T cells, and the development of T cell memory. In summary, the CATCH regimen benefited the enhancement of the CIC by integrating LNP-mRNA formulations and DC therapy. This work presents a promising immunotherapy strategy that exhibits efficacious treatment potential for primary tumor, tumor metastasis, and tumor recurrence.

Fig. 1 | Illustration of closing the cancer-immunity cycle by integrating lipid nanoparticle-mRNA formulations and dendritic cell therapy (CATCH). This illustration was created with BioRender.com.

Our paper: Zhang, Y., Hou, X., Du, S., Xue, Y., Yan, J., Kang, D. D., Zhong, Y., Wang, C., Deng, B., McComb, D. W., Dong, Y*., Close the Cancer-Immunity Cycle by integrating lipid nanoparticle-mRNA formulations and dendritic cell therapy, Nature Nanotechnology, 2023. https://www.nature.com/articles/s41565-023-01453-9

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