Sphingosine-1-phosphate receptor type 1 (S1P1) loss mediated T-cell sequestration in bone marrow amidst glioblastoma (GBM): a novel mode of cancer-induced immunosuppression


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Pakawat Chongsathidkiet1,Samuel Harrison Farber1,Karolina Woroniecka1,Aladine Elsamadicy1,Xiuyu Cui1,Peter Fecci1
1Duke University

Abstract

Background

Glioblastoma (GBM), the most lethal primary brain tumor, proves one of the most immunosuppressive solid tumors, limiting efficacy for immune-based interventions. We have found lymphopenia, systemic T-cell dysfunction, and lymphoid organ retraction in treatment-naïve patients and mice with GBM. Furthermore, we have demonstrated that missing T-cells are sequestered in large numbers in the bone marrow (BM). Sphingosine-1-phosphate receptor type 1 (S1P1) normally regulates T-cell trafficking out of spleen, thymus, and lymph node, but can control egress from BM in mice lacking these lymphoid organs, as seen with GBM.

Method

Whole blood, BM aspirates, and tumors were collected from 15 treatment-naïve GBM patients and 15 age-matched controls. Wild-type and S1P1 knock-in murine models of intracranial and subcutaneous tumors were established. Blood, lymphoid organs, and tumors were harvested. Specimens are labeled with relevant antibodies and analyzed by flow cytometry.

Results

BM-sequestered T-cells showed decreased surface S1P1 expression in GBM compared to controls. Interestingly, sequestration characterized not only GBM, but various other malignancies (lung, melanoma, and breast), although only when tumors were situated intracranially. A strong inverse relationship was observed between T-cell S1P1 levels and T-cell counts in BM across all tumor models (r=-0.65; p<0.0001). Forced S1P1 loss on T-cells was sufficient to elicit their rapid sequestration in GBM-bearing mice, while mice knocked-in for stabilized T-cell S1P1 demonstrated abrogated sequestration. Reversing sequestration alone conveyed a survival benefit in murine GBM with accompanying increased numbers of activated tumor-infiltrating lymphocytes.

Conclusion

Here we discover a novel mode of cancer-induced T-cell dysfunction contributed specifically by the intracranial microenvironment: S1P1-mediated BM T-cell sequestration. These findings suggest that the immunoprivileged brain harbors unique mechanisms, usurped by intracranial tumors, for preventing T-cell entry into the CNS to favor immune escape. Reversal of such sequestration is anticipated as a promising immunotherapeutic adjunct for both primary brain tumors and brain metastases.