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Effective Anti-tumor Response by TIGIT Blockade Associated With Fc?R Engagement and Myeloid Cell Activation.

ABSTRACT: The molecule "T cell immunoreceptor with immunoglobulin and ITIM domain," or TIGIT, has recently received much attention as a promising target in the treatment of various malignancies. In spite of the quick progression of anti-TIGIT antibodies into clinical testing both as monotherapy and in combination with programmed cell death-1 (PD-1)-directed immune checkpoint blockade, the molecular mechanism behind the observed therapeutic benefits remains poorly understood. Here we demonstrate, using mouse tumor models, that TIGIT blocking antibodies with functional Fc binding potential induce effective anti-tumor response. Our observations reveal that the anti-TIGIT therapeutic effect is not achieved by depletion of intratumoral regulatory T cells (Treg) or any cell population expressing TIGIT, but instead is mediated by possible "reverse activating signals" through Fc?Rs on myeloid cells, inducing expression of various mediators such as cytokines and chemokines. Furthermore, we discovered an induction of a robust and persistent granzyme B and perforin response, distinct from a predominantly interferon-? (IFN-?)-driven anti-PD-1 blockade. Our observations, for the first time, provide the basis for a mechanistic hypothesis involving the requirement of a functional Fc domain of anti-TIGIT monoclonal antibodies, of which various isotypes are currently under intense clinical investigation.

SUBMITTER: Han JH

PROVIDER: S-EPMC7577118 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Effective Anti-tumor Response by TIGIT Blockade Associated With FcγR Engagement and Myeloid Cell Activation.

Han Jin-Hwan JH Cai Mingmei M Grein Jeffery J Perera Samanthi S Wang Hongmei H Bigler Mike M Ueda Roenna R Rosahl Thomas W TW Pinheiro Elaine E LaFace Drake D Seghezzi Wolfgang W Williams Sybil M Genther SMG

Frontiers in immunology 20201007

The molecule "T cell immunoreceptor with immunoglobulin and ITIM domain," or TIGIT, has recently received much attention as a promising target in the treatment of various malignancies. In spite of the quick progression of anti-TIGIT antibodies into clinical testing both as monotherapy and in combination with programmed cell death-1 (PD-1)-directed immune checkpoint blockade, the molecular mechanism behind the observed therapeutic benefits remains poorly understood. Here we demonstrate, using mou ...[more]

PMID: 33117369

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Project description:IL-21-αHSA combined with TIGIT blockade induces an effective anti-tumor immune response, indicated by the significant enrichment of pathways associated with anti-tumor immune response, as well as significantly increased expression of key genes associated with CD8+ T and NK cell cytotoxicity To further understand the mechanisms by which IL-21-αHSA enhances the benefit of TIGIT blockade, we analyzed MC38 tumor tissues 20 days after five doses of both single agent and combination treatments by RNA sequencing (RNA-seq) of 28,758 genes. Compared to isotype control treatment, combination treatment resulted in 764 genes with differential expression (defined as P < 0.05 and fold change > 2.0), while IL-21-αHSA treatment resulted in 402 DEGs and anti-mTIGIT treatment resulted in 528 DEGs (data not shown). These findings suggest that the combination treatment had a more dramatic effect on gene expression than IL-21-αHSA or anti-mTIGIT treatment alone. To evaluate the pathways underlying the synergistic anti-tumor efficacy induced by the combination treatment, we performed Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway significance enrichment analysis (defined as P adjust < 0.05). In comparison to the isotype control treatment, 41 KEGG pathways were significantly enriched in the combination treatment group (Table S1) and 31 pathways were significantly enriched in the IL-21-αHSA treatment group (Table S2), of which 28 KEGG enrichment pathways overlapped. Additionally, only 8 KEGG pathways were significantly enriched in the anti-mTIGIT treatment group (Table S3), of which 5 KEGG enrichment pathways overlapped with those of the combination treatment group. These findings suggest that IL-21-αHSA in combination with anti-mTIGIT treatment enriched more KEGG pathways with differential gene expression than for monotherapy, and most of the KEGG pathways significantly enriched by the combination treatment were also differentially enriched by IL-21-αHSA treatment alone. The top 15 pathways, ranked in order of significance, are shown in Fig. 7A. As expected, most are associated with classical anti-tumor immunity signal pathways, including the cytokine-cytokine receptor interaction pathway, the viral protein interaction with cytokine and cytokine receptor pathway, the Th1 and Th2 cell differentiation pathway, the antigen processing and presentation pathway, the T cell receptor signaling pathway, and the PD-L1 expression and PD-1 checkpoint pathway in cancer (P adjust < 0.0001). The natural killer cell mediated cytotoxicity pathway was also significantly enriched (P adjust = 0.0059) in the combination treatment group compared to isotype control treatment group, but was not among the top 15 pathways. Overall, these findings suggest that IL-21-αHSA in combination with TIGIT blockade treatment significantly affects the anti-tumor immunity signal in the tumor micro-environment. For further verification, we analyzed the gene expression levels of key effector molecules, including Interferon-γ (IFNG), Granzyme A (Gzma), Granzyme B (Gzmb), and Perforin 1 (Prf1), each of which are critical mediators of CD8+ T cell and NK cell cytotoxicity and are known to play critical roles in anti-tumor response. As shown in Fig. 7B-E, the combination treatment significantly increased the expression of all four genes (P < 0.05) relative to isotype control treatment, though only IFNG and Gzma were differentially expressed in the combination treatment group relative to the anti-mTIGIT group (P < 0.05). Collectively, these results suggest that IL-21-αHSA in combination with TIGIT blockade induces an effective anti-tumor immune response, indicated by the significant enrichment of pathways associated with anti-tumor immune response, as well as significantly increased expression of key genes associated with CD8+ T and NK cell cytotoxicity.

Project description:Coinhibition of TIGIT (T cell immunoreceptor with Ig and ITIM domains) and PD-1/PD-L1 (PD-1/L1) may improve response rates compared with monotherapy PD-1/L1 blockade in checkpoint naive non-small cell lung cancer with PD-L1 expression >50%. TIGIT mAbs with an effector-competent Fc can induce myeloid cell activation, and some have demonstrated effector T cell depletion, which carries a clinical liability of unknown significance. TIGIT Ab blockade translates to antitumor activity by enabling PVR signaling through CD226 (DNAM-1), which can be directly inhibited by PD-1. Furthermore, DNAM-1 is downregulated on tumor-infiltrating lymphocytes (TILs) in advanced and checkpoint inhibition-resistant cancers. Therefore, broadening clinical responses from TIGIT blockade into PD-L1low or checkpoint inhibition-resistant tumors, may be induced by immune costimulation that operates independently from PD-1/L1 inhibition. TNFSF14 (LIGHT) was identified through genomic screens, in vitro functional analysis, and immune profiling of TILs as a TNF ligand that could provide broad immune activation. Accordingly, murine and human bifunctional fusion proteins were engineered linking the extracellular domain of TIGIT to the extracellular domain of LIGHT, yielding TIGIT-Fc-LIGHT. TIGIT competitively inhibited binding to all PVR ligands. LIGHT directly activated myeloid cells through interactions with LTβR (lymphotoxin β receptor), without the requirement for a competent Fc domain to engage Fcγ receptors. LIGHT costimulated CD8+ T and NK cells through HVEM (herpes virus entry mediator A). Importantly, HVEM was more widely expressed than DNAM-1 on T memory stem cells and TILs across a range of tumor types. Taken together, the mechanisms of TIGIT-Fc-LIGHT promoted strong antitumor activity in preclinical tumor models of primary and acquired resistance to PD-1 blockade, suggesting that immune costimulation mediated by LIGHT may broaden the clinical utility of TIGIT blockade.

Dataset Information

Effective Anti-tumor Response by TIGIT Blockade Associated With Fc?R Engagement and Myeloid Cell Activation.

Publications

Effective Anti-tumor Response by TIGIT Blockade Associated With FcγR Engagement and Myeloid Cell Activation.

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