Pancreatic ductal adenocarcinoma (PDAC), immunomodulation, ablative therapy (AT), radiofrequency ablation (RFA), irreversible electroporation (IRE), histotripsy, radiotherapy (RT)


Pancreatic ductal adenocarcinoma (PDAC) accounts for over 90% of pancreatic cancers. Every year, we face approximately 500,000 new PDAC patients and almost the same number of deaths from this devastating disease both in men and women. The dismal prognosis can be attributed to the immunosuppressive composition of the tumor microenvironment, causing antitumor immune response inhibition, resulting in pancreatic cancer initiation, insidious and rapid progression, and dissemination. The dense desmoplastic stroma, an essential component of the cancer microenvironment, is acting as a physical barrier manifesting in treatment-insensitive pancreatic cancer. Disruption of the dense and immunosuppressive stroma with radio and ablative therapies gives us promising results as the possible inductor and enhancer of an antitumor immune response. In this review, we discuss stromal-targeting ablation methods along with radiotherapy as a dense stromal environment destruction tool and activator of antitumor immune response in pancreatic cancer patients.


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Siegel RL, Miller KD, Fuchs HE, Jemal A. Cancer statistics, 2022. CA Cancer J Clin. 2022;72: 7–33.

Stoffel EM, McKernin SE, Brand R, Canto M, Goggins M, Moravek C, et al. Evaluating Susceptibility to Pancreatic Cancer: ASCO Provisional Clinical Opinion. J Clin Oncol. 2019;37: 153–164.

Suker M, Beumer BR, Sadot E, Marthey L, Faris JE, Mellon EA, et al. FOLFIRINOX for locally advanced pancreatic cancer: a systematic review and patient-level meta-analysis. Lancet Oncol. 2016;17: 801–810.

Janssen QP, van Dam JL, Doppenberg D, Prakash LR, van Eijck CHJ, Jarnagin WR, et al. FOLFIRINOX as Initial Treatment for Localized Pancreatic Adenocarcinoma: A Retrospective Analysis by the Trans-Atlantic Pancreatic Surgery (TAPS) Consortium. J Natl Cancer Inst. 2022. doi:10.1093/jnci/djac018

Ghaneh P, Palmer DH, Cicconi S, Halloran C, Psarelli EE, Rawcliffe CL, et al. ESPAC-5F: Four-arm, prospective, multicenter, international randomized phase II trial of immediate surgery compared with neoadjuvant gemcitabine plus capecitabine (GEMCAP) or FOLFIRINOX or chemoradiotherapy (CRT) in patients with borderline resectable pancreatic cancer. J Clin Orthod. 2020;38: 4505–4505.

Sohal DPS, Kennedy EB, Cinar P, Conroy T, Copur MS, Crane CH, et al. Metastatic Pancreatic Cancer: ASCO Guideline Update. J Clin Oncol. 2020; JCO2001364.

van Dam JL, Janssen QP, Besselink MG, Homs MYV, van Santvoort HC, van Tienhoven G, et al. Neoadjuvant therapy or upfront surgery for resectable and borderline resectable pancreatic cancer: A meta-analysis of randomised controlled trials. Eur J Cancer. 2022;160: 140–149.

Carlos Fernandez-del Castillo, MDRamon E Jimenez, MDJanet E Murphy, MD, MPH. Supportive care of the patient with locally advanced or metastatic exocrine pancreatic cancer. Savarese DMF, editor. UpToDate; 2021.

Tempero MA, Malafa MP, Al-Hawary M, Behrman SW, Benson AB, Cardin DB, et al. Pancreatic Adenocarcinoma, Version 2.2021, NCCN Clinical Practice Guidelines in Oncology. J Natl Compr Canc Netw. 2021;19: 439–457.

Adamska A, Domenichini A, Falasca M. Pancreatic Ductal Adenocarcinoma: Current and Evolving Therapies. Int J Mol Sci. 2017;18. doi:10.3390/ijms18071338

Xu Z, Pothula SP, Wilson JS, Apte MV. Pancreatic cancer and its stroma: a conspiracy theory. World J Gastroenterol. 2014;20: 11216–11229.

Wang Z, Li Y, Kong D, Banerjee S, Ahmad A, Azmi AS, et al. Acquisition of epithelial-mesenchymal transition phenotype of gemcitabine-resistant pancreatic cancer cells is linked with activation of the notch signaling pathway. Cancer Res. 2009;69: 2400–2407.

Mullendore ME, Koorstra J-B, Li Y-M, Offerhaus GJ, Fan X, Henderson CM, et al. Ligand-dependent Notch signaling is involved in tumor initiation and tumor maintenance in pancreatic cancer. Clin Cancer Res. 2009;15: 2291–2301.

Timmer FEF, Geboers B, Nieuwenhuizen S, Dijkstra M, Schouten EAC, Puijk RS, et al. Pancreatic Cancer and Immunotherapy: A Clinical Overview. Cancers . 2021;13. doi:10.3390/cancers13164138

Mucciolo G, Roux C, Scagliotti A, Brugiapaglia S, Novelli F, Cappello P. The dark side of immunotherapy: pancreatic cancer. Cancer Drug Resistance. 2020;3: 491–520.

Tempero MA. NCCN Guidelines Updates: Pancreatic Cancer. J Natl Compr Canc Netw. 2019;17: 603–605.

Rawla P, Sunkara T, Gaduputi V. Epidemiology of Pancreatic Cancer: Global Trends, Etiology and Risk Factors. World J Oncol. 2019;10: 10–27.

Orth M, Metzger P, Gerum S, Mayerle J, Schneider G, Belka C, et al. Pancreatic ductal adenocarcinoma: biological hallmarks, current status, and future perspectives of combined modality treatment approaches. Radiat Oncol. 2019;14: 141.

Ajina R, Weiner LM. T-Cell Immunity in Pancreatic Cancer. Pancreas. 2020;49: 1014–1023.

Muller M, Haghnejad V, Schaefer M, Gauchotte G, Caron B, Peyrin-Biroulet L, et al. The Immune Landscape of Human Pancreatic Ductal Carcinoma: Key Players, Clinical Implications, and Challenges. Cancers . 2022;14. doi:10.3390/cancers14040995

Wu Y, Zhang C, Jiang K, Werner J, Bazhin AV, D’Haese JG. The Role of Stellate Cells in Pancreatic Ductal Adenocarcinoma: Targeting Perspectives. Front Oncol. 2020;10: 621937.

Clark CE, Hingorani SR, Mick R, Combs C, Tuveson DA, Vonderheide RH. Dynamics of the immune reaction to pancreatic cancer from inception to invasion. Cancer Res. 2007;67: 9518–9527.

Ino Y, Yamazaki-Itoh R, Shimada K, Iwasaki M, Kosuge T, Kanai Y, et al. Immune cell infiltration as an indicator of the immune microenvironment of pancreatic cancer. Br J Cancer. 2013;108: 914–923.

Wang Y, Lin H-C, Huang M-Y, Shao Q, Wang Z-Q, Wang F-H, et al. The Immunoscore system predicts prognosis after liver metastasectomy in colorectal cancer liver metastases. Cancer Immunol Immunother. 2018;67: 435–444.

Fukunaga A, Miyamoto M, Cho Y, Murakami S, Kawarada Y, Oshikiri T, et al. CD8+ tumor-infiltrating lymphocytes together with CD4+ tumor-infiltrating lymphocytes and dendritic cells improve the prognosis of patients with pancreatic adenocarcinoma. Pancreas. 2004;28: e26–31.

Huber M, Brehm CU, Gress TM, Buchholz M, Alashkar Alhamwe B, von Strandmann EP, et al. The Immune Microenvironment in Pancreatic Cancer. Int J Mol Sci. 2020;21. doi:10.3390/ijms21197307

Chen Z, Moyana T, Saxena A, Warrington R, Jia Z, Xiang J. Efficient antitumor immunity derived from maturation of dendritic cells that had phagocytosed apoptotic/necrotic tumor cells. Int J Cancer. 2001;93: 539–548.

Kotera Y, Shimizu K, Mulé JJ. Comparative analysis of necrotic and apoptotic tumor cells as a source of antigen(s) in dendritic cell-based immunization. Cancer Res. 2001;61: 8105–8109.

Melcher A, Gough M, Todryk S, Vile R. Apoptosis or necrosis for tumor immunotherapy: what’s in a name? J Mol Med . 1999;77: 824–833.

Takaki H, Cornelis F, Kako Y, Kobayashi K, Kamikonya N, Yamakado K. Thermal ablation and immunomodulation: From preclinical experiments to clinical trials. Diagn Interv Imaging. 2017;98: 651–659.

Bernstein MB, Krishnan S, Hodge JW, Chang JY. Immunotherapy and stereotactic ablative radiotherapy (ISABR): a curative approach? Nat Rev Clin Oncol. 2016;13: 516–524.

Shigematsu A, Adachi Y, Koike-Kiriyama N, Suzuki Y, Iwasaki M, Koike Y, et al. Effects of low-dose irradiation on enhancement of immunity by dendritic cells. J Radiat Res. 2007;48: 51–55.

Clark PA, Sriramaneni RN, Bates AM, Jin WJ, Jagodinsky JC, Hernandez R, et al. Low-Dose Radiation Potentiates the Propagation of Anti-Tumor Immunity against Melanoma Tumor in the Brain after In Situ Vaccination at a Tumor outside the Brain. Radiat Res. 2021;195: 522–540.

Yu P, Rowley DA, Fu Y-X, Schreiber H. The role of stroma in immune recognition and destruction of well-established solid tumors. Curr Opin Immunol. 2006;18: 226–231.

Liu Y, Dong Y, Kong L, Shi F, Zhu H, Yu J. Abscopal effect of radiotherapy combined with immune checkpoint inhibitors. J Hematol Oncol. 2018;11: 104.

Formenti SC, Demaria S. Systemic effects of local radiotherapy. Lancet Oncol. 2009;10: 718–726.

Kroemer G, Galluzzi L, Kepp O, Zitvogel L. Immunogenic cell death in cancer therapy. Annu Rev Immunol. 2013;31: 51–72.

Reits EA, Hodge JW, Herberts CA, Groothuis TA, Chakraborty M, Wansley EK, et al. Radiation modulates the peptide repertoire, enhances MHC class I expression, and induces successful antitumor immunotherapy. J Exp Med. 2006;203: 1259–1271.

Swamy K. Stereotactic Body Radiotherapy Immunological Planning—A Review With a Proposed Theoretical Model. Frontiers in Oncology. 2022. doi:10.3389/fonc.2022.729250

Ma Y, Aymeric L, Locher C, Kroemer G, Zitvogel L. The dendritic cell-tumor cross-talk in cancer. Curr Opin Immunol. 2011;23: 146–152.

McBride WH, Chiang C-S, Olson JL, Wang C-C, Hong J-H, Pajonk F, et al. A sense of danger from radiation. Radiat Res. 2004;162: 1–19.

Hodge JW, Ardiani A, Farsaci B, Kwilas AR, Gameiro SR. The tipping point for combination therapy: cancer vaccines with radiation, chemotherapy, or targeted small molecule inhibitors. Semin Oncol. 2012;39: 323–339.

Reyngold M, O’Reilly E, Zinovoy M, Romesser PB, Wu AJ, Hajj C, et al. Ablative RT Results in Excellent Local Control and Survival in Localized Pancreatic Cancer. International Journal of Radiation Oncology*Biology*Physics. 2019. p. S206. doi:10.1016/j.ijrobp.2019.06.276

Hall WA, Goodman KA. Radiation therapy for pancreatic adenocarcinoma, a treatment option that must be considered in the management of a devastating malignancy. Radiat Oncol. 2019;14: 114.

Krishnan S, Rana V, Janjan NA, Varadhachary GR, Abbruzzese JL, Das P, et al. Induction chemotherapy selects patients with locally advanced, unresectable pancreatic cancer for optimal benefit from consolidative chemoradiation therapy. Cancer. 2007;110: 47–55.

Ma SJ, Prezzano KM, Hermann GM, Singh AK. Dose escalation of radiation therapy with or without induction chemotherapy for unresectable locally advanced pancreatic cancer. Radiation Oncology. 2018. doi:10.1186/s13014-018-1158-z

Lee Y-H, Yu C-F, Yang Y-C, Hong J-H, Chiang C-S. Ablative Radiotherapy Reprograms the Tumor Microenvironment of a Pancreatic Tumor in Favoring the Immune Checkpoint Blockade Therapy. Int J Mol Sci. 2021;22. doi:10.3390/ijms22042091

Yousaf MN, Ehsan H, Muneeb A, Wahab A, Sana MK, Neupane K, et al. Role of Radiofrequency Ablation in the Management of Unresectable Pancreatic Cancer. Front Med. 2020;7: 624997.

Mizandari M, Kumar J, Pai M, Chikovani T, Azrumelashvili T, Reccia I, et al. Interventional radiofrequency ablation: A promising therapeutic modality in the management of malignant biliary and pancreatic duct obstruction. J Cancer. 2018;9: 629–637.

Faraoni EY, Thosani NC, O’Brien B, Strickland LN, Mota V, Chaney J, et al. Radiofrequency ablation remodels the tumor microenvironment and promotes systemic immunomodulation in pancreatic cancer. bioRxiv. 2022. p. 2022.01.07.475451. doi:10.1101/2022.01.07.475451

Fei Q, Pan Y, Lin W, Zhou Y, Yu X, Hou Z, et al. High-dimensional single-cell analysis delineates radiofrequency ablation induced immune microenvironmental remodeling in pancreatic cancer. Cell Death Dis. 2020;11: 589.

Geboers B, Ruarus AH, Nieuwenhuizen S, Puijk RS, Scheffer HJ, de Gruijl TD, et al. Needle-guided ablation of locally advanced pancreatic cancer: cytoreduction or immunomodulation by in vivo vaccination? Chin Clin Oncol. 2019;8: 61.

den Brok MHMGM, Sutmuller RPM, Nierkens S, Bennink EJ, Frielink C, Toonen LWJ, et al. Efficient loading of dendritic cells following cryo and radiofrequency ablation in combination with immune modulation induces anti-tumour immunity. Br J Cancer. 2006;95: 896–905.

Bhardwaj N, Dormer J, Ahmad F, Strickland AD, Gravante G, Beckingham I, et al. Heat shock protein 70 expression following hepatic radiofrequency ablation is affected by adjacent vasculature. J Surg Res. 2012;173: 249–257.

Dromi SA, Walsh MP, Herby S, Traughber B, Xie J, Sharma KV, et al. Radiofrequency ablation induces antigen-presenting cell infiltration and amplification of weak tumor-induced immunity. Radiology. 2009;251: 58–66.

Schneider T, Hoffmann H, Dienemann H, Herpel E, Heussel CP, Enk AH, et al. Immune Response After Radiofrequency Ablation and Surgical Resection in Nonsmall Cell Lung Cancer. Semin Thorac Cardiovasc Surg. 2016;28: 585–592.

Giardino A, Innamorati G, Ugel S, Perbellini O, Girelli R, Frigerio I, et al. Immunomodulation after radiofrequency ablation of locally advanced pancreatic cancer by monitoring the immune response in 10 patients. Pancreatology. 2017;17: 962–966.

He C, Wang J, Sun S, Zhang Y, Li S. Immunomodulatory Effect after Irreversible Electroporation in Patients with Locally Advanced Pancreatic Cancer. J Oncol. 2019;2019: 9346017.

Pandit H, Hong YK, Li Y, Rostas J, Pulliam Z, Li SP, et al. Evaluating the Regulatory Immunomodulation Effect of Irreversible Electroporation (IRE) in Pancreatic Adenocarcinoma. AnnSurgOncol.2019;26:800–6.

Bader KB, Vlaisavljevich E, Maxwell AD. For Whom the Bubble Grows: Physical Principles of Bubble Nucleation and Dynamics in Histotripsy Ultrasound Therapy. Ultrasound Med Biol. 2019;45: 1056–1080.61.

Qu S, Worlikar T, Felsted AE, Ganguly A, Beems MV, Hubbard R, et al. Non-thermal histotripsy tumor ablation promotes abscopal immune responses that enhance cancer immunotherapy. J Immunother Cancer. 2020;8: e000200.

Nam G-H, Pahk KJ, Jeon S, Park H-J, Kim GB, Oh SJ, et al. Investigation of the Potential Immunological Effects of Boiling Histotripsy for Cancer Treatment. Advanced Therapeutics. 2020;3: 1900214.

Xu Z, Hall TL, Vlaisavljevich E, Lee FT. Histotripsy: the first noninvasive, non-ionizing, non-thermal ablation technique based on ultrasound. Int J Hyperthermia. 2021;38: 561–575.

Hendricks AD, Brock RM, Gannon J, Zeher A, Sereno J, Vlaisavljevich E, et al. Determining the mechanism of the immune response to histotripsy ablation of pancreatic cancer. The Journal of Immunology. 2020;204: 241.2–241.2.




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