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标题：Harnessing anti-cytomegalovirus immunity for local immunotherapy against solid tumors
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作者：Nicolas Çuburu ; Lukasz Bialkowski ; Sergio M. Pontejo 等
期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2022
卷号：119
期号：26
DOI：10.1073/pnas.2116738119
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：Significance Harnessing the heterogeneity of the cancer antigenic landscape to induce antitumor T cells is at the basis of personalized vaccines and adoptive T cell–transfer therapies. However, these highly personalized approaches remain associated with limited efficacy against most solid tumors and manufacturing complexities, whose high costs of development and implementation have limited their impact as public health interventions. Using murine cancer models, we report a tumor antigen–agnostic approach based on intratumoral injection of virus-derived peptide epitopes to mobilize vigorous antiviral T cell responses. This strategy does not require the characterization of tumor-associated antigens, and it can mobilize vigorous, cytotoxic T cell responses in the tumor microenvironment and promote epitope spreading against tumor-associated antigens. Tumor infiltration by T cells profoundly affects cancer progression and responses to immunotherapy. However, the tumor immunosuppressive microenvironment can impair the induction, trafficking, and local activity of antitumor T cells. Here, we investigated whether intratumoral injection of virus-derived peptide epitopes could activate preexisting antiviral T cell responses locally and promote antitumor responses or antigen spreading. We focused on a mouse model of cytomegalovirus (CMV), a highly prevalent human infection that induces vigorous and durable T cell responses. Mice persistently infected with murine CMV (MCMV) were challenged with lung (TC-1), colon (MC-38), or melanoma (B16-F10) tumor cells. Intratumoral injection of MCMV-derived T cell epitopes triggered in situ and systemic expansion of their cognate, MCMV-specific CD4 + or CD8 + T cells. The MCMV CD8 + T cell epitopes injected alone provoked arrest of tumor growth and some durable remissions. Intratumoral injection of MCMV CD4 + T cell epitopes with polyinosinic acid:polycytidylic acid (pI:C) preferentially elicited tumor antigen–specific CD8 + T cells, promoted tumor clearance, and conferred long-term protection against tumor rechallenge. Notably, secondary proliferation of MCMV-specific CD8 + T cells correlated with better tumor control. Importantly, intratumoral injection of MCMV-derived CD8 + T cell–peptide epitopes alone or CD4 + T cell–peptide epitopes with pI:C induced potent adaptive and innate immune activation of the tumor microenvironment. Thus, CMV-derived peptide epitopes, delivered intratumorally, act as cytotoxic and immunotherapeutic agents to promote immediate tumor control and long-term antitumor immunity that could be used as a stand-alone therapy. The tumor antigen–agnostic nature of this approach makes it applicable across a broad range of solid tumors regardless of their origin.
关键词：enantiviral immunityintratumoral immunotherapycytomegalovirusantigen spreadingtumor microenvironment