CTLA-4/CD80 pathway regulates T cell infiltration into pancreatic cancer
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The ability of some tumors to exclude effector T cells represents a major challenge to immunotherapy. T cell exclusion is particularly evident in pancreatic ductal adenocarcinoma (PDAC), a disease where blockade of the immune checkpoint molecule CTLA-4 has not produced significant clinical activity. In PDAC, effector T cells are often scarce within tumor tissue and confined to peritumoral lymph nodes and lymphoid aggregates. We hypothesized that CTLA-4 blockade, despite a lack of clinical efficacy seen thus far in PDAC, might still alter T cell immunobiology, which would have therapeutic implications. Using clinically relevant genetic models of PDAC, we found that regulatory T cells (Tregs), which constitutively express CTLA-4, accumulate early during tumor development but are largely confined to peritumoral lymph nodes during disease progression. Tregs were observed to regulate CD4+, but not CD8+, T cell infiltration into tumors through a CTLA-4/CD80 dependent mechanism. Disrupting CTLA-4 interaction with CD80 was sufficient to induce CD4 T cell infiltration into tumors. These data have important implications for T cell immunotherapy in PDAC and demonstrate a novel role for CTLA-4/CD80 interactions in regulating T cell exclusion. In addition, our findings suggest distinct mechanisms govern CD4+ and CD8+ T cell infiltration in PDAC.
KeywordsPancreas cancer T cell exclusion Treg CTLA-4 CD80 Immunotherapy
Cytotoxic lymphocyte-associated antigen-4
LSL-Kras G12D/+;LSL-Trp53 R172H/+; Pdx-1Cre
Pancreatic intraepithelial neoplasia
Pancreatic ductal adenocarcinoma
Regulatory T cell
The authors thank Patrick Guirnalda for helpful discussion and Adam Bedenbaugh for advice and technical assistance with immunohistochemistry assays.
Compliance with ethical standards
Support for this project was provided by the following grants from the National Institutes of Health and National Cancer Institute: K08 CA138907 (Gregory L. Beatty) and R01 CA197916 (Gregory L. Beatty). We are grateful to the Molecular Biology and Molecular Pathology and Imaging Cores of the Penn Center supported by a Molecular Studies in Digestive and Liver Diseases grant from the National Institutes of Health. This work was also supported by the following foundations and agencies: AACR-PanCAN Career Development Award (Florencia McAllister), National Pancreas Foundation (Florencia McAllister), Department of Defense Discovery Award (Gregory Beatty), and the Damon Runyon Cancer Research Foundation Innovation Award supported by the Nadia’s Gift Foundation (Gregory Beatty).
Conflict of interest
The authors declare that they have no conflict of interest.
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