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Generation of Orthotopic Pancreatic Tumors and Ex vivo Characterization of Tumor-Infiltrating T Cell Cytotoxicity
Published on: December 7, 2019
Defined tumor antigen-specific T cells potentiate personalized TCR-T cell therapy and prediction of immunotherapy
Jingjing He1,2, Xinxin Xiong1,2, Han Yang1
1State Key Laboratory of Oncology in Southern China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China.
Abstract:
Personalized immunotherapy targeting tumor-specific antigens (TSAs) could generate efficient and safe antitumor immune response without damaging normal tissues. Although neoantigen vaccines have shown therapeutic effect in clinic trials, precise prediction of neoantigens from tumor mutations is still challenging. The host antitumor immune response selects and activates T cells recognizing tumor antigens. Hence, T cells engineered with T-cell receptors (TCRs) from these naturally occurring tumor antigen-specific T (Tas) cells in a patient will target personal TSAs in his/her tumor. To establish such a personalized TCR-T cell therapy, we comprehensively characterized T cells in tumor and its adjacent tissues by single-cell mRNA sequencing (scRNA-seq), TCR sequencing (TCR-seq) and in vitro neoantigen stimulation. Compared to bystander T cells circulating among tissues, Tas cells were characterized by tumor enrichment, tumor-specific clonal expansion and neoantigen specificity. We found that CXCL13 is a unique marker for both CD4+ and CD8+ Tas cells. Importantly, TCR-T cells expressing TCRs from Tas cells showed significant therapeutic effects on autologous patient-derived xenograft (PDX) tumors. Intratumoral Tas cell levels measured by CXCL13 expression precisely predicted the response to immune checkpoint blockade, indicating a critical role of Tas cells in the antitumor immunity. We further identified CD200 and ENTPD1 as surface markers for CD4+ and CD8+ Tas cells respectively, which enabled the isolation of Tas cells from tumor by Fluorescence Activating Cell Sorter (FACS) sorting. Overall, our results suggest that TCR-T cells engineered with Tas TCRs are a promising agent for personalized immunotherapy, and intratumoral Tas cell levels determine the response to immunotherapy.
Insights
Personalized immunotherapy using T-cell receptors (TCRs) from tumor-specific T cells shows promise. Identifying tumor antigen-specific T cells and their TCRs enables effective, targeted cancer treatments and predicts immunotherapy response.
Area of Science:
- Immunology
- Oncology
- Biotechnology
Background:
- Personalized immunotherapy aims to target tumor-specific antigens (TSAs) for effective and safe antitumor responses.
- Predicting neoantigens from tumor mutations remains a challenge for current neoantigen vaccines.
- Naturally occurring tumor antigen-specific T (Tas) cells possess T-cell receptors (TCRs) that target personal TSAs.
Purpose of the Study:
- To characterize T cells within tumors and adjacent tissues to identify tumor antigen-specific T (Tas) cells.
- To establish a personalized T-cell receptor (TCR)-T cell therapy using TCRs from patient-derived Tas cells.
- To determine if Tas cell levels can predict response to cancer immunotherapy.
Main Methods:
- Comprehensive characterization of T cells using single-cell mRNA sequencing (scRNA-seq) and TCR sequencing (TCR-seq).
- In vitro neoantigen stimulation assays to confirm T-cell specificity.
- Development and testing of T-cell receptor (TCR)-T cell therapy in patient-derived xenograft (PDX) models.
- Identification of surface markers (CXCL13, CD200, ENTPD1) for Tas cell isolation via Fluorescence-Activated Cell Sorting (FACS).
Main Results:
- Tas cells exhibited tumor enrichment, tumor-specific clonal expansion, and neoantigen specificity compared to bystander T cells.
- CXCL13 was identified as a unique marker for both CD4+ and CD8+ Tas cells.
- TCR-T cells engineered with Tas TCRs demonstrated significant therapeutic effects against autologous PDX tumors.
- Intratumoral Tas cell levels, indicated by CXCL13 expression, accurately predicted response to immune checkpoint blockade.
- CD200 and ENTPD1 were identified as specific surface markers for CD4+ and CD8+ Tas cells, respectively, enabling FACS isolation.
Conclusions:
- TCR-T cells engineered with Tas TCRs represent a promising strategy for personalized immunotherapy.
- Intratumoral Tas cell abundance is a critical determinant of response to immunotherapy, including immune checkpoint blockade.
- The identification of specific surface markers facilitates the isolation of functional Tas cells for therapeutic development.
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