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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: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:PurposeStereotactic body radiation therapy (SBRT) is a promising treatment modality for locally advanced pancreatic cancer (LAPC). We evaluated the clinical outcomes of SBRT in patients with LAPC.Patients and methodsWe retrospectively analyzed the medical records of patients with LAPC who underwent SBRT at our institution between April 2011 and July 2016. Fiducial markers were implanted using endoscopic ultrasound guidance one week prior to 4-dimensional computed tomography (CT) simulation and daily cone beam CT was used for image guidance. Patients received volumetric modulated arc therapy or intensity modulated radiotherapy using respiratory gating technique. A median dose of 28 Gy (range, 24-36 Gy) was given over four consecutive fractions delivered within one week. Survival outcomes including freedom from local disease progression (FFLP), progression-free survival (PFS), and overall survival (OS) were analyzed. Acute and late toxicities related to SBRT were assessed.ResultsA total of 95 patients with LAPC were analyzed, 52 of which (54.7%) had pancreatic head cancers. Most (94.7%) had received gemcitabine-based chemotherapy. The 1-year FFLP rate was 80.1%. Median OS and PFS were 16.7 months and 10.2 months, respectively; the 1-year OS and PFS rates were 67.4% and 42.9%, respectively. Among 79 patients who experienced failure, the sites of first failures were isolated local progressions in 12 patients (15.2%), distant metastasis in 55 patients (69.6%), and both in 12 patients (15.2%). Seven patients (7.4%) were able to undergo surgical resection after SBRT and four had margin-negative resections. Three patients (3.2%) had grade 3 nausea/vomiting during SBRT, and late grade 3 toxicity was observed in another three patients.ConclusionsLAPC patients who received chemotherapy and SBRT had favorable FFLP and OS with minimal treatment-related toxicity. The most common pattern of failure was distant metastasis, which warrants further studies on the optimal scheme of chemotherapy and SBRT.
| S-EPMC6461258 | biostudies-literature
Project description:BACKGROUND:While clinical outcomes following induction chemotherapy and stereotactic body radiation therapy (SBRT) have been reported for borderline resectable pancreatic cancer (BRPC) patients, pathologic response has not previously been described. METHODS:This single-institution retrospective review evaluated BRPC patients who completed induction gemcitabine-based chemotherapy followed by SBRT and surgical resection. Each surgical specimen was assigned two tumor regression grades (TRG), one using the College of American Pathologists (CAP) criteria and one using the MD Anderson Cancer Center (MDACC) criteria. Overall survival (OS) and progression free survival (PFS) were correlated to TRG score. RESULTS:We evaluated 36 patients with a median follow-up of 13.8 months (range, 6.1-24.8 months). The most common induction chemotherapy regimen (82%) was GTX (gemcitabine, docetaxel, capecitabine). A median SBRT dose of 35 Gy (range, 30-40 Gy) in 5 fractions was delivered to the region of vascular involvement. The margin-negative resection rate was 97.2%. Improved response according to MDACC grade trended towards superior PFS (P=061), but not OS. Any neoadjuvant treatment effect according to MDACC scoring (IIa-IV vs. I) was associated with improved OS and PFS (both P=0.019). We found no relationship between CAP score and OS or PFS. CONCLUSIONS:These data suggest that the increased pathologic response after induction chemotherapy and SBRT is correlated with improved survival for BRPC patients.
| S-EPMC4783738 | biostudies-literature
Project description:Introduction:Pancreatic adenocarcinoma is an aggressive malignancy that has consistently demonstrated poor outcomes despite aggressive treatments. Despite multimodal treatment, local disease progression and local recurrence are common. Management of recurrent or progressive pancreatic carcinomas proves a further challenge. In patients previously treated with radiation therapy, stereotactic body radiation therapy (SBRT) is a promising modality capable of delivering high dose to the tumor while limiting dose to critical structures. We aimed to determine the feasibility and tolerability of SBRT for recurrent or local pancreatic cancer in patients previously treated with external beam radiation therapy (EBRT). Materials and methods:Patients treated with EBRT who developed recurrent or local pancreatic ductal adenocarcinoma treated with SBRT reirradiation at our institution, from 2004 to 2014 were reviewed. Our primary endpoints included overall survival (OS), local control, regional control, and late grade 3+ radiation toxicity. Endpoints were analyzed with the Kaplan-Meier method. The association of these survival endpoints with risk factors was studied with univariate Cox proportional hazards models. Results:We identified 38 patients with recurrent/progressive pancreatic cancer treated with SBRT following prior radiation therapy. Prior radiation was delivered to a median dose of 50.4?Gy in 28 fractions. SBRT was delivered to a median dose of 24.5?Gy in 1-3 fractions. Surgical resection was performed on 55.3% of all patients. Within a median follow-up of 24.4?months (inter-quartile range, 14.9-32.7?months), the median OS from diagnosis for the entire cohort was 26.6?months (95% CI: 20.3-29.8) with 2-year OS of 53.0%. Median survival from SBRT was 9.7?months (95% CI, 5.5-13.8). The 2-year freedom from local progression and regional progression was 58 and 82%, respectively. For the entire cohort, 18.4 and 10.5% experienced late grade 2+ and grade 3+ toxicity, respectively. Conclusion:This single institution retrospective review identified SBRT reirradiation to be a feasible and tolerable treatment strategy for patients with previous locally progressive or recurrent pancreatic adenocarcinoma.
| S-EPMC5845878 | biostudies-literature
Project description:BACKGROUND:The LAP07 randomized trial calls into question the role of radiation therapy (RT) in the modern treatment of locally advanced pancreatic cancer (LAPC). However, advances in chemotherapy and RT limit application of the LAP07 results to current clinical practice. Here we utilize the National Cancer Database (NCDB) to evaluate the effects of RT in patients receiving chemotherapy for LAPC. METHODS:Using the NCDB, patients with American Joint Committee on Cancer (AJCC) clinical stage T2-4, N0-1, M0 adenocarcinoma of the pancreas from 2004 to 2014 were analyzed. Patients were stratified into chemotherapy only (CT) and chemoradiation (CRT) cohorts. Patients undergoing definitive RT, defined as at least 20 fractions or ? 5 Gy per fraction [i.e., stereotactic body radiation therapy (SBRT)] were included in the CRT cohort. Propensity-score matching (PSM) and landmark analysis were used to address selection bias and lead-time bias, respectively. RESULTS:13,004 patients met inclusion criteria, of whom 7034 (54%) received CT and 5970 (46%) received CRT. After PSM, 5215 patients remained in each cohort. The CRT cohort demonstrated better overall survival (OS) compared with CT alone, with median and 1-year OS of 12 versus 10 months, and 50% and 41%, respectively (p < 0.001). On multivariable analysis, CRT was associated with superior OS with hazard ratio of 0.79 (95% confidence interval 0.76-0.83) compared with CT alone. CONCLUSIONS:In our series, addition of definitive radiotherapy to CT was associated with better OS when compared with CT alone in LAPC. Definitive radiotherapy should remain a treatment option for LAPC, but optimal selection criteria remain unclear.
| S-EPMC5951381 | biostudies-literature
Project description:Pancreatic cancer is a formidable malignancy with poor outcomes. The majority of patients are unable to undergo resection, which remains the only potentially curative treatment option. The management of locally advanced (unresectable) pancreatic cancer is controversial; however, treatment with either chemotherapy or chemoradiation is associated with high rates of local tumor progression and metastases development, resulting in low survival rates. An emerging local modality is stereotactic body radiation therapy (SBRT), which uses image-guided, conformal, high-dose radiation. SBRT has demonstrated promising local control rates and resultant quality of life with acceptable rates of toxicity. Over the past decade, increasing clinical experience and data have supported SBRT as a local treatment modality. Nevertheless, additional research is required to further evaluate the role of SBRT and improve upon the persistently poor outcomes associated with pancreatic cancer. This review discusses the existing clinical experience and technical implementation of SBRT for pancreatic cancer and highlights the directions for ongoing and future studies.
| S-EPMC5096771 | biostudies-literature
Project description:Standard doses of conventionally fractionated radiation have had minimal to no impact on the survival duration of patients with locally advanced unresectable pancreatic cancer (LAPC). The use of low-dose stereotactic body radiation (SBRT) in 3- to 5-fractionshas thus far produced a modest improvement in median survival with minimal toxicity and shorter duration of treatment, but failed to produce a meaningful difference at 2 years and beyond. A much higher biologically effective dose (BED) is likely needed to achieve tumor ablation The challenge is the delivery of ablative doses near the very sensitive gastrointestinal tract. Advanced organ motion management, image guidance, and adaptive planning techniques enable delivery of ablative doses of radiation (> = 100Gy BED) when more protracted hypofractionated regimens or advanced image guidance and adaptive planning are used. This approach has resulted in encouraging improvements in survival in several studies. This review will summarize the evolution of the radiation technique over time from conventional to ablative and describe the practical aspects of delivering ablative doses near the GI tract using cone beam CT image (CBCT) guidance and online adaptive MRI guidance.
| S-EPMC6555709 | biostudies-literature