Absence of Toll-like receptor 5 confers survival in mice bearing ovarian tumors treated with anti-PD-L1
Abstract Ovarian cancer accounts for more deaths than any other cancer of the female reproductive system. Patients bearing ovarian tumors infiltrated with high frequencies of T cells associate with a greater survival probability. However, therapeutic strategies targeting T cells in ovarian cancers a...
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Published in | The Journal of immunology (1950) Vol. 208; no. 1_Supplement; pp. 120 - 120.05 |
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Main Authors | , , , , |
Format | Journal Article |
Language | English |
Published |
01.05.2022
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Online Access | Get full text |
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Summary: | Abstract
Ovarian cancer accounts for more deaths than any other cancer of the female reproductive system. Patients bearing ovarian tumors infiltrated with high frequencies of T cells associate with a greater survival probability. However, therapeutic strategies targeting T cells in ovarian cancers are largely ineffective. We have observed in our models of late-stage murine ovarian cancer that in the absence of Toll-Like Receptor 5 (TLR5) signaling, anti-PD-L1 therapy promotes significant survival and subsequent protection against tumor rechallenge. Ovarian tumors from rechallenged TLR5KO mice exhibited significantly higher frequency/number of both CD4 and CD8 effector memory T cell subsets and greater numbers of antigen experienced T cells. Thus, in the absence of TLR5 signaling, T cells are better able to mount/maintain a response to ovarian tumors after inhibitory receptor blockade. Furthermore, protection against tumor progression in TLR5KO mice corresponds with a significant increase in tumor infiltrating cross presenting and IL-12 producing Dendritic cells (DCs) which could account for the differences in T cell infiltrates. We hypothesize that TLR5 signaling functionally alters DCs to become more suppressive in the tumor microenvironment, impacting T cell differentiation and anti-tumor activity, thereby reducing survival during ovarian tumor progression with aPD-L1 therapy. Clinical implications are already present, as roughly 7.5% of the general population harbor a TLR5 SNP that diminishes TLR5 signaling and is associated with increased long-term survival for ovarian cancer patients. Therefore, patients who express the TLR5 SNP may immediately benefit from anti-PDL1 therapy and those without the SNP, TLR5 antagonism.
Supported by NIH/NCI 1R01CA253285 UVA CIC Collaborative Grant |
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ISSN: | 0022-1767 1550-6606 |
DOI: | 10.4049/jimmunol.208.Supp.120.05 |