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Project description: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.
| S-EPMC10224952 | biostudies-literature
Project description:Radiation therapy induces immunogenic cell death in cancer cells, whereby apoptotic cells release endogenous adjuvants that are sensed by immune cells to direct adaptive immune responses. Toll-like receptors (TLRs) expressed on several immune subtypes recognize these products to direct downstream responses in part via the adapter protein MyD88. Here we use lineage specific deletion of Myd88 to interrogate its contribution to the immune response to radiation therapy in distinct immune populations in pancreatic cancer. While Myd88 deletion in Itgax- and Lck-expressing immune populations had little discernable effects on response to radiation therapy, Lyz2-specific loss of Myd88 rendered tumors more susceptible to radiation therapy dependent on CD8+ T cells. scRNAseq revealed gene signatures in myeloid and dendritic cells indicative of enhanced type I and II interferon responses. Together, these data implicate MyD88 signaling in myeloid cells as a critical source of immunosuppression that hinders adaptive immune tumor control following radiation therapy.
2023-08-28 | GSE176014 | GEO
Project description:Radiation therapy induces immunogenic cell death in cancer cells, whereby apoptotic cells release endogenous adjuvants that are sensed by immune cells to direct adaptive immune responses. Toll-like receptors (TLRs) expressed on several immune subtypes recognize these products to direct downstream responses in part via the adapter protein MyD88. Here we use lineage specific deletion of Myd88 to interrogate its contribution to the immune response to radiation therapy in distinct immune populations in pancreatic cancer. While Myd88 deletion in Itgax- and Lck-expressing immune populations had little discernable effects on response to radiation therapy, Lyz2-specific loss of Myd88 rendered tumors more susceptible to radiation therapy dependent on CD8+ T cells. scRNAseq revealed gene signatures in myeloid and dendritic cells indicative of enhanced type I and II interferon responses. Together, these data implicate MyD88 signaling in myeloid cells as a critical source of immunosuppression that hinders adaptive immune tumor control following radiation therapy.
2023-08-28 | GSE176011 | GEO
Project description:Myeloid MyD88 restricts CD8+ T cell response to radiation therapy in pancreatic cancer
| PRJNA734581 | ENA
Project description:Myeloid MyD88 restricts CD8+ T cell response to radiation therapy in pancreatic cancer [Nanostring]
| PRJNA734585 | ENA
Project description:Myeloid MyD88 restricts CD8+ T cell response to radiation therapy in pancreatic cancer [sequencing]
| PRJNA734576 | ENA
Project description:ObjectivePancreatic ductal adenocarcinoma (PDAC) is a deadly malignancy, due in large part to its resistance to conventional therapies, including radiotherapy (RT). Despite RT exerting a modest antitumor response, it has also been shown to promote an immunosuppressive tumor microenvironment. Previous studies demonstrated that focal adhesion kinase inhibitors (FAKi) in clinical development inhibit the infiltration of suppressive myeloid cells and T regulatory (T regs) cells, and subsequently enhance effector T cell infiltration. FAK inhibitors in clinical development have not been investigated in combination with RT in preclinical murine models or clinical studies. Thus, we investigated the impact of FAK inhibition on RT, its potential as an RT sensitizer and immunomodulator in a murine model of PDAC.MethodsWe used a syngeneic orthotopic murine model to study the effect of FAKi on hypofractionated RT.ResultsIn this study we showed that IN10018, a small molecular FAKi, enhanced antitumor response to RT. Antitumor activity of the combination of FAKi and RT is T cell dependent. FAKi in combination with RT enhanced CD8+ T cell infiltration significantly in comparison to the radiation or FAKi treatment alone (P < 0.05). FAKi in combination with radiation inhibited the infiltration of granulocytes but enhanced the infiltration of macrophages and T regs in comparison with the radiation or FAKi treatment alone (P < 0.01).ConclusionsThese results support the clinical development of FAKi as a radiosensitizer for PDAC and combining FAKi with RT to prime the tumor microenvironment of PDAC for immunotherapy.
| S-EPMC7877172 | biostudies-literature
Project description:Pancreatic cancer has a dismal prognosis with an overall survival outcome of just 5% at five years. However, paralleling our improved understanding of the biology of pancreatic cancer, treatment paradigms have also continued to evolve with newer advances in surgical techniques, chemotherapeutic agents, radiation therapy (RT) techniques, and immunotherapy paradigms. RT dose, modality, fraction size, and sequencing are being evaluated actively, and the interplay between RT and immune effects has opened up newer avenues of research. In this review, we will emphasize recent advances in RT for pancreatic cancer, focusing on preoperative chemoradiation, RT dose escalation, sparing of the spleen to reduce lymphopenia, and combination of RT with immunotherapy.
| S-EPMC6305239 | biostudies-literature
Project description:In todays practice most institutions individualize the use of adjuvant, neoadjuvant, and definitive RT based on their interpretation of the available data. This review highlights novel concepts and approaches to the use of RT that should be considered by the surgical oncologist.
| S-EPMC8462521 | biostudies-literature
Project description:BackgroundPancreatic cancer has highly aggressive features, such as local recurrence that leads to significantly high morbidity and mortality and recurrence after successful tumour resection. Intraoperative radiation therapy (IORT), which delivers targeted radiation to a tumour bed, is known to reduce local recurrence by directly killing tumour cells and modifying the tumour microenvironment.MethodsAmong 30 patients diagnosed with pancreatic cancer, 17 patients received IORT immediately after surgical resection. We investigated changes in the immune response induced by IORT by analysing the peritoneal fluid (PF) and blood of patients with and without IORT treatment after pancreatic cancer surgery. Further, we treated three pancreatic cell lines with PF to observe proliferation and activity changes.ResultsLevels of cytokines involved in the PI3K/SMAD pathway were increased in the PF of IORT-treated patients. Moreover, IORT-treated PF inhibited the growth, migration, and invasiveness of pancreatic cancer cells. Changes in lymphocyte populations in the blood of IORT-treated patients indicated an increased immune response.ConclusionsBased on the characterisation and quantification of immune cells in the blood and cytokine levels in the PF, we conclude that IORT induced an anti-tumour effect by activating the immune response, which may prevent pancreatic cancer recurrence.Clinical trial registrationNCT03273374 .
| S-EPMC8507125 | biostudies-literature