Inhibigens™ drive pro-tumor responses and may act through non-classical inhibitory mechanisms

Abstract The ATLAS™ platform screens a patient’s tumor mutanome with autologous T cells and antigen presenting cells to identify targets for cancer immunotherapy. Tumor mutations that lead to increased T cell responses are deemed stimulatory (neoantigens), while those rendering decreased responses a...

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Bibliographic Details
Published inThe Journal of immunology (1950) Vol. 206; no. 1_Supplement; pp. 29 - 29.06
Main Authors DeVault, Victoria L, Starobinets, Hanna, Arnold, Julie, Rinaldi, Stephanie, Odeh, Osaruese, Nguyen, Cindy, Flechtner, Jessica B, Lam, Hubert
Format Journal Article
LanguageEnglish
Published 01.05.2021
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Summary:Abstract The ATLAS™ platform screens a patient’s tumor mutanome with autologous T cells and antigen presenting cells to identify targets for cancer immunotherapy. Tumor mutations that lead to increased T cell responses are deemed stimulatory (neoantigens), while those rendering decreased responses are defined as Inhibigens. In B16F10 mouse melanoma, therapeutic neoantigen vaccination resulted in durable protection, while Inhibigen co-administration resulted in a remarkable reversal of protection and abrogation of anti-tumor responses. The Inhibigen-related pro-tumor effects were not reduced by αPD-1 therapy, and administration of αCTLA-4 resulted in modest benefit, suggesting that Inhibigen-specific responses can overpower current standard-of-care immunotherapies. The tumor microenvironment of Inhibigen-vaccinated mice was immune cold, with dramatic decreases in infiltrating T cells and myeloid cells relative to controls. Inhibigen effects were not associated with classical inhibitory mechanisms such as an overabundance of CD4+CD25+Foxp3+Tregs, MHC competition or downregulation. In addition, T cell proliferation appeared unaffected by Inhibigen administration. Time course experiments revealed that Inhibigen-specific phenotypes (e.g. defective T cell IFNγ production) occur as early as 4 days post vaccination, suggesting deficiencies related to T cell priming. RNAseq analyses showed distinct changes in T cell transcriptional patterns between neoantigen and Inhibigen-experienced T cells. Taken together, these data reveal a potential non-classical inhibitory mechanism by which responses to naturally occurring cancer mutations may promote tumor growth and reverse beneficial anti-tumor immune responses.
ISSN:0022-1767
1550-6606
DOI:10.4049/jimmunol.206.Supp.29.06