Myeloid MyD88 restricts CD8 + T cell response to radiation therapy in pancreatic cancer.

Autor: Medler TR; 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., Blair TC; 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., Alice AF; 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., Dowdell AK; 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., Piening BD; 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., Crittenden MR; 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, USA., Gough MJ; 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. michael.gough@providence.org.
Jazyk: angličtina
Zdroj: Scientific reports [Sci Rep] 2023 May 27; Vol. 13 (1), pp. 8634. Date of Electronic Publication: 2023 May 27.
DOI: 10.1038/s41598-023-35834-w
Abstrakt: 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/Myd88 fl/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.
(© 2023. The Author(s).)
Databáze: MEDLINE
Externí odkaz:
Nepřihlášeným uživatelům se plný text nezobrazuje