Targeting myeloid-derived suppressor cells and the PD-1/PD-L1 axis to enhance immunotherapy with anti-CEA designer T cells for the treatment of colorectal liver metastases
Abstract only 3079 Background: Immunotherapy for colorectal cancer liver metastases (CRCLM) is limited by the intrahepatic immunosuppressive environment mediated in part by myeloid derived suppressor cells (MDSC), which expand in response to tumor. T cell suppression can be mediated by programmed de...
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Published in | Journal of clinical oncology Vol. 31; no. 15_suppl; p. 3079 |
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Main Authors | , , , , , , |
Format | Journal Article |
Language | English |
Published |
20.05.2013
|
Online Access | Get full text |
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Summary: | Abstract only
3079
Background: Immunotherapy for colorectal cancer liver metastases (CRCLM) is limited by the intrahepatic immunosuppressive environment mediated in part by myeloid derived suppressor cells (MDSC), which expand in response to tumor. T cell suppression can be mediated by programmed death ligand-1 (PD-L1, CD274) on MDSC binding to programmed death-1 (PD-1, CD279) on T cells. We hypothesize blocking PD-L1 will improve adoptive cellular therapy efficacy for CRCLM through inhibition of MDSC-mediated T cell suppression. Methods: “Designer” T cells (dTc) were produced from activated murine splenocytes transduced with chimeric antigen receptor (CAR) specific for CEA. C57BL/6 mice were injected with CEA
+
MC38 tumor cells via spleen, and liver MDSC (CD11b
+
Gr1
+
) were purified with immunomagnetic beads after two weeks. MDSC were co-cultured with stimulated dTc with or without in vitro PD-L1 blockade. Results: MDSC expanded 2.4-fold in response to CRCLM, and expressed high levels of PD-L1 (63.8% PD-L1
+
). PD-L1 was equally expressed on both monocytic (CD11b
+
Ly6G
-
Ly6C
+
) and granulocytic (CD11b
+
Ly6G
+
) MDSC subsets (43.6% PD-L1
+
and 27.9% PD-L1
+
, respectively). Expression of related ligand, PD-L2 was found to be negligible in both subsets. The cognate inhibitory receptor, PD-1, was expressed on dTc (23.8% PD-1
+
) and native T cells (37.3% PD-1
+
). Increasing endogenous T cell expression of PD-1 significantly correlated with MDSC expansion (r=0.9774, p<0.0001) in response to CRCLM. Co-culture of dTc with MDSC demonstrated the suppressive effect of MDSC on dTc proliferation which was abrogated with in vitro targeting of PD-L1. The percentage of dTc proliferating in the presence of CEA
+
tumor decreased from 72.2% to 29.3% (p<0.001) with the addition of MDSC, and immunosuppression was reversed with blockade of PD-L1, which resulted in a 1.6-fold increase in dTc proliferation (p=0.01 ). Conclusions: Liver MDSC expand in the presence of CRCLM and mediate suppression of anti-CEA dTc via PD-L1. Our results indicate that blockade of PD-L1:PD-1 engagement is a viable strategy for enhancing the efficacy of adoptive cell therapy for liver metastases. |
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ISSN: | 0732-183X 1527-7755 |
DOI: | 10.1200/jco.2013.31.15_suppl.3079 |