Development of cancer immunotherapeutic strategies based on a multi-dimensional understanding of cancer immunology

Abstract

The field of cancer immunotherapy has seen significant advancements over recent decades, including the development of cancer neoantigen vaccines that elicit systemic tumor-specific immune responses; immune checkpoint inhibitors (ICIs) that reinvigorate the activity of tumor-specific immune cells; chimeric antigen receptor T-cell (CAR-T) therapy, which introduces substantial numbers of tumor-specific T cells for tumor eradication; and antibody-based treatments that facilitate tumor-targeting attacks. However, tumor-induced immunosuppression and resistance within the tumor microenvironment (TME) limit the efficacy of these therapies. Additionally, cancer is increasingly recognized as a systemic disease, characterized by alterations in immune status throughout the body. These factors underscore the necessity for developing cancer therapeutics that holistically address both systemic and intratumoral immune activation. This study explores novel cancer therapeutic strategies through a more comprehensive understanding of cancer immunology. Initially, we developed a neoantigen vaccine to systemically activate tumor-specific immune responses and effectively optimize the TME by activating invariant natural killer T (iNKT) cells using α-Galactosylceramide (α-GalCer), thereby achieving enhanced tumor treatment outcomes. Although this approach reversed inhibitory immune cells, it could not overcome tumor heterogeneity. Consequently, we introduced allogeneic major histocompatibility complex (MHC) molecules within tumors to label the tumor and enhance its recognizability while optimizing the TME. However, this strategy lacked the corresponding systemic immune response activation, affecting its overall efficacy. To address these challenges, we further optimized our strategy to concurrently activate both systemic and intratumoral immunity. Our research demonstrated that incorporating a step to systemically activate immunity against the same allogeneic MHC significantly improved therapeutic outcomes. To further enhance treatment efficacy, we replaced the introduction of allogeneic MHC with pathogen-derived antigens, thereby increasing the tumor's antigenicity and immunogenicity. Our data showed that using an mRNA vaccine platform to establish a systemic pathogen-derived antigen-specific immune response, followed by introducing the same antigen into the tumor, effectively marked tumor cells with pathogen-derived antigen proteins and rapidly activated systemic pathogen-derived antigen-specific immune responses that targeted the marked tumor cells. The subsequent eradication of these cells triggered antigen spreading, inducing broader tumor-specific immune responses against heterogeneous tumor cells. This strategy induces both systemic and intratumoral immune activation while reprogramming the TME and overcoming tumor heterogeneity. Consequently, this pathogen-derived antigen mRNA vaccine-based cancer immunotherapy shows promise as a potent, broad-spectrum, off-the-shelf treatment. It also offers the potential to achieve multiple cancer treatment goals with a single drug, providing fertile ground for subsequent cancer therapies or combination treatments. Given that most of the global population has developed immune memory against various pathogens through infection or vaccination, especially against SARS-CoV-2, we predict that mRNA lipid nanoparticle-based vaccines targeting not only SARS-CoV-2 but also other pathogens, such as Hepatitis B Virus (HBV), common human coronaviruses (HCoVs), and the influenza virus, could also offer a comprehensive immunotherapy strategy for various cancers. The extensive selection of pathogen-derived antigens expands therapeutic opportunities and reduces the potential for drug resistance. We believe this therapeutic approach could be rapidly transitioned into clinical use, providing a promising alternative for cancer patients and paving the way for future combinational treatments.