The design of efficacious and cost-effective therapeutic vaccines against cancer remains both a research priority and a challenge. For more than a decade, our laboratory has been involved in the development of synthetic peptide-based anti-cancer therapeutic vaccines. We first dedicated our efforts in the identification and validation of peptide epitopes for both CD8 and CD4 T cells from tumor-associated antigens (TAAs). Because of suboptimal immune responses and lack of therapeutic benefit of peptide vaccines containing these epitopes, we have focused our recent efforts in optimizing peptide vaccinations in mouse tumor models using numerous TAA epitopes. In this focused research review, we describe how after taking lessons from the immune system’s way of dealing with acute viral infections, we have designed peptide vaccination strategies capable of generating very high numbers of therapeutically effective CD8 T cells. We also discuss some of the remaining challenges to translate these findings into the clinical setting.
BackgroundImmunotherapies, such as immune checkpoint inhibitors and adoptive cell therapies, have revolutionized cancer treatment and resulted in complete and durable responses in some patients. Unfortunately, most immunotherapy treated patients still fail to respond. Absence of T cell infiltration to the tumor site is one of the major obstacles limiting immunotherapy efficacy against solid tumors. Thus, the development of strategies that enhance T cell infiltration and broaden the antitumor efficacy of immunotherapies is greatly needed.MethodsWe used mouse tumor models, genetically deficient mice and vascular endothelial cells (VECs) to study the requirements for T cell infiltration into tumors.ResultsA specific formulation of poly-IC, containing poly-lysine and carboxymethylcellulose (PICLC) facilitated the traffic and infiltration of effector CD8 T cells into the tumors that reduced tumor growth. Surprisingly, intratumoral injection of PICLC was significantly less effective in inducing tumor T cell infiltration and controlling growth of tumors as compared with systemic (intravenous or intramuscular) administration. Systemically administered PICLC, but not poly-IC stimulated tumor VECs via the double-stranded RNA cytoplasmic sensor MDA5, resulting in enhanced adhesion molecule expression and the production of type I interferon (IFN-I) and T cell recruiting chemokines. Expression of IFNαβ receptor in VECs was necessary to obtain the antitumor effects by PICLC and IFN-I was found to directly stimulate the secretion of T cell recruiting chemokines by VECs indicating that this cytokine-chemokine regulatory axis is crucial for recruiting effector T cells into the tumor parenchyma. Unexpectedly, these effects of PICLC were mostly observed in tumors and not in normal tissues.ConclusionsThese findings have strong implications for the improvement of all types of T cell-based immunotherapies for solid cancers. We predict that systemic administration of PICLC will improve immune checkpoint inhibitor therapy, adoptive cell therapies and therapeutic cancer vaccines.
Background: Recent advances in immunotherapy have revolutionized cancer treatment. Immune checkpoint blockade and adoptive T cell therapy can induce durable responses in some patients. However, the majority of patients fail to respond. Absence of T cell infiltration to the tumor site in solid tumors is considered as one of the major obstacles for effective immunotherapy. Thus, strategies to enhance T cell trafficking and infiltration into the tumor parenchyma is a major research need. Methods: Using a combination of in vivo mouse tumor models and in vitro assays we compared the capacity of various formulations and routes of administration of poly-IC (a dsRNA mimic that functions as a pattern recognition receptor ligand) in enhancing T cell tumor infiltration and generating antitumor responses. Results: Our results showed that poly-ICLC (poly-IC containing poly-lysine and carboxymethylcellulose) enhanced CD8 T cell infiltration into the tumors resulting in the control of tumor growth. These effects relied both on the route of administration as well as on the formulation of poly-IC. Systemic administration (i.v. or i.m.) of poly-ICLC was significantly more effective in inducing CD8 T cell tumor infiltration as compared to intra-tumoral injections. Also, the effects poly-ICLC were substantially more pronounced as compared to unmodified poly-IC. The antitumor effect of poly-ICLC was mediated via MDA-5 and IFN-I, whereas TLR3 stimulation was not required. Interestingly, poly-ICLC stimulated IFN-I responses on tumor vascular endothelial cells (VECs) enhancing the expression of adhesion molecules (VCAM-I), production of IFN-I and T cell recruiting chemokines (CXCL9/CXCL10). Using conditional knockout mice, showed that ablation of IFNab receptors in VECs impaired the antitumor effects of poly-ICLC. IFN-I production upon MDA5 stimulation is required to enhance the secretion of (CXCL9/CXCL10) by VECs indicating that this IFN-I/CXCL9/CXCL10 regulatory axis is crucial for recruiting effector T cells into the tumor parenchyma. The T cell infiltrating effects of poly-ICLC were mainly observed in tumors and not in normal tissues. Conclusions: Systemic administration of poly-ICLC improves T cell infiltration to solid tumors in an MDA5/IFN-I dependent manner. These findings should have a strong impact on improving T cell-based treatments for solid cancers such as adoptive T cell therapy and antitumor vaccines. Citation Format: Hussein Sultan, Juan Wu, Valentyna Fesenkova, Aaron Fan, Diane Addis, Andres Salazar, Esteban Celis. Systemic administration of Poly-ICLC promotes T cell tumor infiltration generating antitumor responses [abstract]. In: Abstracts: AACR Virtual Special Conference: Tumor Immunology and Immunotherapy; 2020 Oct 19-20. Philadelphia (PA): AACR; Cancer Immunol Res 2021;9(2 Suppl):Abstract nr PO011.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.