Radiation Therapy Exacerbates Tumor-Promoting Innervation and Nerve Signaling in Rectal Cancer

Uccello, Taylor P.; Lecsh, Maggie L.; Ullman, Nicholas A.; Kintzel, Sarah A.; Gradzewicz, Lauren B.; Velagaleti, Trishna; Fleming, Fergal J.; Mills, Bradley N.; Murphy, Joseph D.; Garrett-Larsen, Jesse; Qiu, Haoming; Drage, Michael G.; Ye, Jian; Gavras, Nicholas W.; Johnston, Carl J.; Love, Tanzy; Repasky, Elizabeth A.; Linehan, David C.; Lord, Edith M.; Uccello, Taylor P.

doi:10.1016/j.ijrobp.2022.09.080

Cited by 2 publications

(2 citation statements)

References 35 publications

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“…Tumors were harvested on day 14 following SCRT, weighed, designated as responders or nonresponders, and prepared for bulk sequencing [ 9 ]. Tumor-associated macrophages (TAMs; CD45+, CD11b+, Ly6C−, Ly6G−, F480+), CD8 + T cells (CD45+, CD8b+), MC38-GFP tumor cells (CD45− GFP+) and cancer-associated fibroblasts (CAFs; CD45 − CD31 − GFP − PDGFRα + Podoplanin + Ly6C + ) were sequenced.…”

Section: Methodsmentioning

confidence: 99%

New insights into the responder/nonresponder divide in rectal cancer: Damage-induced Type I IFNs dictate treatment efficacy and can be targeted to enhance radiotherapy

Lesch¹,

Kintzel²,

Gradzewicz³

et al. 2023

Cell Death Dis

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Rectal cancer ranks as the second leading cause of cancer-related deaths. Neoadjuvant therapy for rectal cancer patients often results in individuals that respond well to therapy and those that respond poorly, requiring life-altering excision surgery. It is inadequately understood what dictates this responder/nonresponder divide. Our major aim is to identify what factors in the tumor microenvironment drive a fraction of rectal cancer patients to respond to radiotherapy. We also sought to distinguish potential biomarkers that would indicate a positive response to therapy and design combinatorial therapeutics to enhance radiotherapy efficacy. To address this, we developed an orthotopic murine model of rectal cancer treated with short course radiotherapy that recapitulates the bimodal response observed in the clinic. We utilized a robust combination of transcriptomics and protein analysis to identify differences between responding and nonresponding tumors. Our mouse model recapitulates human disease in which a fraction of tumors respond to radiotherapy (responders) while the majority are nonresponsive. We determined that responding tumors had increased damage-induced cell death, and a unique immune-activation signature associated with tumor-associated macrophages, cancer-associated fibroblasts, and CD8+ T cells. This signature was dependent on radiation-induced increases of Type I Interferons (IFNs). We investigated a therapeutic approach targeting the cGAS/STING pathway and demonstrated improved response rate following radiotherapy. These results suggest that modulating the Type I IFN pathway has the potential to improve radiation therapy efficacy in RC.

show abstract

Section: Methodsmentioning

confidence: 99%

New insights into the responder/nonresponder divide in rectal cancer: Damage-induced Type I IFNs dictate treatment efficacy and can be targeted to enhance radiotherapy

Lesch¹,

Kintzel²,

Gradzewicz³

et al. 2023

Cell Death Dis

Self Cite

View full text Add to dashboard Cite

show abstract

“…Tumors were harvested on day 14 following SCRT, weighed, designated as responders or nonresponders, and prepared for bulk sequencing (9). Tumor-associated macrophages (TAMs; CD45+, CD11b +, Ly6C-, Ly6G-, F480+), CD8 + T cells (CD45+, CD8b+), MC38-GFP tumor cells (CD45-GFP+) and cancer-associated broblasts (CAFs; CD45 − CD31 − GFP − PDGFR + Podoplanin + Ly6C + ) were sequenced.…”

Section: Rna Sequencing Preparation and Analysismentioning

confidence: 99%

New insights into the responder/nonresponder divide in rectal cancer: Damage-induced Type I IFNs dictate treatment efficacy and can be targeted to enhance radiotherapy

Gerber

Uccello

Lesch

et al. 2023

Preprint

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View full text Add to dashboard Cite

Rectal cancer ranks as the second leading cause of cancer-related deaths. Neoadjuvant therapy for rectal cancer patients often results in individuals that respond well to therapy and those that respond poorly, requiring life-altering excision surgery. It is inadequately understood what dictates this responder/nonresponder divide. Our major aim is to identify what factors in the tumor microenvironment drive a fraction of rectal cancer patients to respond to radiotherapy. We also sought to distinguish potential biomarkers that would indicate a positive response to therapy and design combinatorial therapeutics to enhance radiotherapy efficacy. To address this, we developed an orthotopic murine model of rectal cancer treated with short course radiotherapy that recapitulates the bimodal response observed in the clinic. We utilized a robust combination of transcriptomics and protein analysis to identify differences between responding and nonresponding tumors. Our mouse model recapitulates human disease in which a fraction of tumors respond to radiotherapy (responders) while the majority are nonresponsive. We determined that responding tumors had increased damage-induced cell death, and a unique immune-activation signature associated with tumor-associated macrophages, cancer-associated fibroblasts, and CD8+ T cells. This signature was dependent on radiation-induced increases of Type I interferons (IFNs). We investigated a therapeutic approach targeting the cGAS/STING pathway and demonstrated improved response rate following radiotherapy. These results suggest that modulating the Type I IFN pathway has the potential to improve radiation therapy efficacy in RC.

show abstract

Radiation Therapy Exacerbates Tumor-Promoting Innervation and Nerve Signaling in Rectal Cancer

Cited by 2 publications

References 35 publications

New insights into the responder/nonresponder divide in rectal cancer: Damage-induced Type I IFNs dictate treatment efficacy and can be targeted to enhance radiotherapy

New insights into the responder/nonresponder divide in rectal cancer: Damage-induced Type I IFNs dictate treatment efficacy and can be targeted to enhance radiotherapy

New insights into the responder/nonresponder divide in rectal cancer: Damage-induced Type I IFNs dictate treatment efficacy and can be targeted to enhance radiotherapy

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