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

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.

Tumor-associated characteristics and immune dysregulation in nasopharyngeal carcinoma under the regulation of m7G-related tumor microenvironment cells

“…TLR signaling pathways were abundantly accumulated in Mac_C2 (Supplementary Fig. S3 D), such as MyD88 deficiency (TLR2/4), IRAK4 deficiency (TLR2/4), regulation of TLR by endogenous ligand, and disease associated with the TLR signaling cascade, which were related to the inflammatory mechanisms of in cancers [ 28 , 29 ]. Interestingly, eukaryotic translation-related pathways were accumulated in Mac_C3, including eukaryotic translation elongation, eukaryotic translation initiation, and eukaryotic translation termination (Fig.…”

Clinical application of immunogenic cell death inducers in cancer immunotherapy: turning cold tumors hot

“…Second, some small molecules can cause radioresistance. For example, in the pancreatic cancer model, myeloid MyD88 (a downstream TLR expressed by macrophages and other immune cells) disturbs the production of Type I IFN, which is essential for T-cell activation, thus restricting the immune response to RT ( Medler et al, 2023 ). Sun et al (2022) demonstrated that glioblastoma multiforme cells receiving RT depend on the STAT1-IRF1-CD39 axis to upregulate the expression of CD39 to contribute to radioresistance.…”

The immunogenic radiation and new players in immunotherapy and targeted therapy for head and neck cancer

“…Understanding the pattern of innate adjuvants released by dying cancer cells is critical, since some forms of cell death are differentially immunogenic (21)(22)(23). Similarly, the cell types that respond to these adjuvants and their differentiation dramatically impact the immune consequences of cancer cell death and adjuvant release (24)(25)(26)(27)(28)(29). Thus, if the response to radiation is optimal, cancer cell death will release antigen and adjuvant to promote dendritic cells (DC) maturation to boost existing T-cell responses and generate new T-cell responses.…”

“…It will also generate a pro-inflammatory environment in the tumor to help attract effector T-cells and guide myeloid differentiation into anti-tumor patterns. A suboptimal response will fail to mature DC ( 30 , 31 ), and generate suppressive cytokine release from cells, such as M2-differentiated macrophages in the tumor environment ( 25 ).…”