TY - JOUR
T1 - CTLA-4/CD80 pathway regulates T cell infiltration into pancreatic cancer
AU - Bengsch, Fee
AU - Knoblock, Dawson M.
AU - Liu, Anni
AU - McAllister, Florencia
AU - Beatty, Gregory L.
N1 - Funding Information:
Financial support 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).
Publisher Copyright:
© 2017, Springer-Verlag GmbH Germany.
PY - 2017/12/1
Y1 - 2017/12/1
N2 - 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.
AB - 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.
KW - CD80
KW - CTLA-4
KW - Immunotherapy
KW - Pancreas cancer
KW - T cell exclusion
KW - Treg
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U2 - 10.1007/s00262-017-2053-4
DO - 10.1007/s00262-017-2053-4
M3 - Article
C2 - 28856392
AN - SCOPUS:85028593113
SN - 0340-7004
VL - 66
SP - 1609
EP - 1617
JO - Cancer Immunology, Immunotherapy
JF - Cancer Immunology, Immunotherapy
IS - 12
ER -