Myeloid MyD88 restricts CD8

Publication Title

Sci Rep

Authors

Terry R Medler, Earle A. Chiles Research Institute, Providence Cancer Institute, Robert W. Franz Cancer Center, Providence Portland Medical Center, 4805 NE Glisan Street, Suite 2N100, Portland, OR, 97213, USA.Follow
Tiffany C Blair, Earle A. Chiles Research Institute, Providence Cancer Institute, Robert W. Franz Cancer Center, Providence Portland Medical Center, 4805 NE Glisan Street, Suite 2N100, Portland, OR, 97213, USA.
Alejandro F Alice, Earle A. Chiles Research Institute, Providence Cancer Institute, Robert W. Franz Cancer Center, Providence Portland Medical Center, 4805 NE Glisan Street, Suite 2N100, Portland, OR, 97213, USA.Follow
Alexa K Dowdell, Earle A. Chiles Research Institute, Providence Cancer Institute, Robert W. Franz Cancer Center, Providence Portland Medical Center, 4805 NE Glisan Street, Suite 2N100, Portland, OR, 97213, USA.Follow
Brian D Piening, Earle A. Chiles Research Institute, Providence Cancer Institute, Robert W. Franz Cancer Center, Providence Portland Medical Center, 4805 NE Glisan Street, Suite 2N100, Portland, OR, 97213, USA.Follow
Marka R Crittenden, Earle A. Chiles Research Institute, Providence Cancer Institute, Robert W. Franz Cancer Center, Providence Portland Medical Center, 4805 NE Glisan Street, Suite 2N100, Portland, OR, 97213, USA., The Oregon Clinic, Portland, OR, USAFollow
Michael J Gough, Earle A. Chiles Research Institute, Providence Cancer Institute, Robert W. Franz Cancer Center, Providence Portland Medical Center, 4805 NE Glisan Street, Suite 2N100, Portland, OR, 97213, USA.Follow

Document Type

Article

Publication Date

5-27-2023

Keywords

oregon; chiles

Abstract

Radiation therapy induces immunogenic cell death in cancer cells, whereby released endogenous adjuvants are sensed by immune cells to direct adaptive immune responses. TLRs expressed on several immune subtypes recognize innate adjuvants to direct downstream inflammatory responses in part via the adapter protein MyD88. We generated Myd88 conditional knockout mice to interrogate its contribution to the immune response to radiation therapy in distinct immune populations in pancreatic cancer. Surprisingly, Myd88 deletion in Itgax (CD11c)-expressing dendritic cells had little discernable effects on response to RT in pancreatic cancer and elicited normal T cell responses using a prime/boost vaccination strategy. Myd88 deletion in Lck-expressing T cells resulted in similar or worsened responses to radiation therapy compared to wild-type mice and lacked antigen-specific CD8+ T cell responses from vaccination, similar to observations in Myd88-/- mice. Lyz2-specific loss of Myd88 in myeloid populations rendered tumors more susceptible to radiation therapy and elicited normal CD8+ T cell responses to vaccination. scRNAseq in Lyz2-Cre/Myd88fl/fl mice revealed gene signatures in macrophages and monocytes indicative of enhanced type I and II interferon responses, and improved responses to RT were dependent on CD8+ T cells and IFNAR1. Together, these data implicate MyD88 signaling in myeloid cells as a critical source of immunosuppression that hinders adaptive immune tumor control following radiation therapy.

Clinical Institute

Cancer

Specialty/Research Institute

Earle A. Chiles Research Institute

Specialty/Research Institute

Oncology

DOI

10.1038/s41598-023-35834-w