Modulation of the Human Pancreatic Ductal Adenocarcinoma Immune Microenvironment by Stereotactic Body Radiotherapy

Mills, Bradley N.; Qiu, Haoming; Drage, Michael G.; Chen, Chunmo; Mathew, Jocelyn S; Garrett-Larsen, Jesse; Ye, Jian; Uccello, Taylor P.; Murphy, Joseph D.; Belt, Brian A.; Lord, Edith M.; Katz, Alan W.; Linehan, David C.; Gerber, Scott A.

doi:10.1158/1078-0432.ccr-21-2495

Cited by 47 publications

(52 citation statements)

References 63 publications

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“…We did not evaluate the discrepancy between the biopsy specimen and the resected sample in this study. Of course, the resected specimen underwent radiotherapy, which may cause excessive collagen deposition and structural disorganization by myosin IIA expression and oxidative stress 56,57 . In addition, the regressed tumor tissue is replaced by interstitial fibrosis 58 .…”

Section: Discussionmentioning

confidence: 99%

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Association of the collagen signature with pathological complete response in rectal cancer patients

et al. 2022

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Collagen in the tumor microenvironment is recognized as a potential biomarker for predicting treatment response. This study investigated whether the collagen features are associated with pathological complete response (pCR) in locally advanced rectal cancer (LARC) patients receiving neoadjuvant chemoradiotherapy (nCRT) and develop and validate a prediction model for individualized prediction of pCR. The prediction model was developed in a primary cohort (353 consecutive patients). In total, 142 collagen features were extracted from the multiphoton image of pretreatment biopsy, and the least absolute shrinkage and selection operator (Lasso) regression was applied for feature selection and collagen signature building. A nomogram was developed using multivariable analysis. The performance of the nomogram was assessed with respect to its discrimination, calibration, and clinical utility. An independent cohort (163 consecutive patients) was used to validate the model. The collagen signature comprised four collagen features significantly associated with pCR both in the primary and validation cohorts (p < 0.001). Predictors in the individualized prediction nomogram included the collagen signature and clinicopathological predictors.The nomogram showed good discrimination with area under the ROC curve (AUC)

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Section: Discussionmentioning

confidence: 99%

“…Of course, the resected specimen underwent radiotherapy, which may cause excessive collagen deposition and structural disorganization by myosin IIA expression and oxidative stress. 56,57 In addition, the regressed tumor tissue is replaced by interstitial fibrosis. 58 In short, the collagen structure of the resected specimen…”

Section: Discussionmentioning

confidence: 99%

Association of the collagen signature with pathological complete response in rectal cancer patients

et al. 2022

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“…This is largely the result of a unique PDAC tumor microenvironment (TME) that consists of a dense desmoplastic stroma with abundant immunosuppressive myeloid cells and few antitumor T cells. [9][10][11][12][13][14][15][16][17][18][19] These characteristics dampen the efficacy of most PDAC therapies, including radiotherapy. Therefore, it is likely that SBRT would need to be combined with an immune-stimulating/repolarizing agent in order to achieve full antitumor potential in PDAC.…”

Section: What This Study Addsmentioning

confidence: 99%

Toll-like receptor 7/8 agonist R848 alters the immune tumor microenvironment and enhances SBRT-induced antitumor efficacy in murine models of pancreatic cancer

Mills

Qin

et al. 2022

J Immunother Cancer

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BackgroundStereotactic body radiotherapy (SBRT) has been increasingly used as adjuvant therapy in pancreatic ductal adenocarcinoma (PDAC), and induces immunogenic cell death, which leads to the release of tumor antigen and damage-associated molecular patterns. However, this induction often fails to generate sufficient response to overcome pre-existing tumor microenvironment (TME) immunosuppression. Toll-like receptor (TLR) 7/8 ligands, such as R848, can amplify the effect of tumor vaccines, with recent evidence showing its antitumor effect in pancreatic cancer by modulating the immunosuppressive TME. Therefore, we hypothesized that the combination of R848 and SBRT would improve local and systemic antitumor immune responses by potentiating the antitumor effects of SBRT and reversing the immunosuppressive nature of the PDAC TME.MethodsUsing murine models of orthotopic PDAC, we assessed the combination of intravenous TLR7/8 agonist R848 and local SBRT on tumor growth and immune response in primary pancreatic tumors. Additionally, we employed a hepatic metastatic model to investigate if the combination of SBRT targeting only the primary pancreatic tumor and systemic R848 is effective in controlling established liver metastases.ResultsWe demonstrated that intravenous administration of the TLR7/8 agonist R848, in combination with local SBRT, leads to superior tumor control compared with either treatment alone. The combination of R848 and SBRT results in significant immune activation of the pancreatic TME, including increased tumor antigen-specific CD8+ T cells, decreased regulatory T cells, and enhanced antigen-presenting cells maturation, as well as increased interferon gamma, granzyme B, and CCL5 along with decreased levels of interleukin 4 (IL-4), IL-6, and IL-10. Importantly, the combination of SBRT and systemic R848 also resulted in similar immunostimulatory changes in liver metastases, leading to improved metastatic control. CD8+ T cell depletion studies highlighted the necessity of these effector cells at both the local and hepatic metastatic sites. T cell receptor (TCR) clonotype analysis indicated that systemic R848 not only diversified the TCR repertoire but also conditioned the metastatic foci to facilitate entry of CD8+ T cells generated by SBRT therapy.ConclusionsThese findings suggest that systemic administration of TLR7/8 agonists in combination with SBRT may be a promising avenue for metastatic PDAC treatment.

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“…In the preclinical setting, SBRT was reported to induce immunogenic tumour death in PDAC [ 203 ]. To further support these findings, Mills et al collected samples of patients with resectable PDAC who underwent SBRT a week before surgical resection, and the analysis showed a higher immune-related cell death and lower malignant cell density, compared to samples of patients who did not undergo any interventions before surgery [ 204 ].…”

Section: Locoregional Therapiesmentioning

confidence: 99%

Pancreatic Cancer: Challenges and Opportunities in Locoregional Therapies

Bazeed

Day

Garg

2022

Cancers

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Pancreatic cancer (PC) remains the seventh leading cause of cancer-related deaths worldwide and the third in the United States, making it one of the most lethal solid malignancies. Unfortunately, the symptoms of this disease are not very apparent despite an increasing incidence rate. Therefore, at the time of diagnosis, 45% of patients have already developed metastatic tumours. Due to the aggressive nature of the pancreatic tumours, local interventions are required in addition to first-line treatments. Locoregional interventions affect a specific area of the pancreas to minimize local tumour recurrence and reduce the side effects on surrounding healthy tissues. However, compared to the number of new studies on systemic therapy, very little research has been conducted on localised interventions for PC. To address this unbalanced focus and to shed light on the tremendous potentials of locoregional therapies, this work will provide a detailed discussion of various localised treatment strategies. Most importantly, to the best of our knowledge, the aspect of localised drug delivery systems used in PC was unprecedentedly discussed in this work. This review is meant for researchers and clinicians considering utilizing local therapy for the effective treatment of PC, providing a thorough guide on recent advancements in research and clinical trials toward locoregional interventions, together with the authors’ insight into their potential improvements.

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Modulation of the Human Pancreatic Ductal Adenocarcinoma Immune Microenvironment by Stereotactic Body Radiotherapy

Cited by 47 publications

References 63 publications

Association of the collagen signature with pathological complete response in rectal cancer patients

Association of the collagen signature with pathological complete response in rectal cancer patients

Toll-like receptor 7/8 agonist R848 alters the immune tumor microenvironment and enhances SBRT-induced antitumor efficacy in murine models of pancreatic cancer

Pancreatic Cancer: Challenges and Opportunities in Locoregional Therapies

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