The absence of IL17A favours cytotoxic cell function and improves antigen-specific immunotherapies in pancreatic adenocarcinoma

Abstract

Background and Aims: The pancreatic tumour microenvironment (TME) is a complex ecosystem where tumour cells, cancer-associated fibroblasts and immune cells interact, often in ways that contribute to tumour growth. The role of interleukin (IL17)A in pancreatic cancer progression is now more defined, and it is known to sustain a pro-tumoural microenvironment and inhibit the immune response. Here, we explore the effect of combining IL17A depletion with a cancer vaccine to enhance anti-tumour immunity.

Methods: We used genetically engineered mice proficient or deficient in IL17A, and orthotopically injected mice with pancreatic tumour cells depleted or not in IL17A, to examine the vaccine effects on tumour growth and immune responses. Both humoral and cellular immune responses were analysed following vaccination in IL17A-deficient and control mice.

Results: Mice lacking IL17A—either genetically or through pharmacological depletion—exhibited prolonged survival and smaller tumours, compared to vaccinated controls. Vaccination in IL17A-deficient mice significantly increased the influx of immune cells, including Natural Killer (NK) and effector/memory CD8 T cells, which displayed higher cytotoxic activity. CD8 T-cell depletion in these models notably reduced vaccine efficacy, underscoring the essential role of these cells. NK cell depletion in untreated models further demonstrated NK cells’ critical function in controlling tumour growth when IL17A was absent. Overall, IL17A depletion enhanced both antigen-specific humoral and cellular immune responses, indicating a shift towards a more robust and responsive immune environment.

Conclusions: Our findings reveal that the absence of IL17A in the pancreatic TME reprograms it into a more immune-supportive environment, favouring the recruitment of effector/memory immune cells upon vaccination. This approach paves the way for novel therapeutic combinations in pancreatic cancer, where IL17A depletion may boost both immunotherapy efficacy and anti-tumour responses.

Keywords

cancer vaccine / humoral response / IL17A / pancreatic cancer / tumour immune microenvironment

References

[1] Siegel RL, Giaquinto AN, Jemal A. Cancer statistics, 2024. CA Cancer J Clin. 2024; 74: 12-49.

[2] Kamisawa T, Wood LD, Itoi T, et al. Pancreatic cancer. Lancet. 2016; 388: 73-85.

[3] Zeng S, Pöttler M, Lan B, et al. Chemoresistance in pancreatic cancer. Int J Mol Sci. 2019; 20: 4504.

[4] Mucciolo G, Roux C, Scagliotti A, et al. The dark side of immunotherapy: pancreatic cancer. CDR. 2020; 3(3): 491-520.

[5] Marin-Acevedo JA, Soyano AE, Dholaria B, et al. Cancer immunotherapy beyond immune checkpoint inhibitors. J Hematol Oncol. 2018; 11: 8.

[6] Kabacaoglu D, Ciecielski KJ, Ruess DA, et al. Immune checkpoint inhibition for pancreatic ductal adenocarcinoma: current limitations and future options. Front Immunol. 2018; 9: 1878.

[7] Falcomatà C, Bärthel S, Schneider G, et al. Context-specific determinants of the immunosuppressive tumor microenvironment in pancreatic cancer. Cancer Discov. 2023; 13: 278-297.

[8] Helms E, Onate MK, Sherman MH. Fibroblast heterogeneity in the pancreatic tumor microenvironment. Cancer Discov. 2020; 10: 648-656.

[9] Mucciolo G, Curcio C, Roux C, et al. IL17A critically shapes the transcriptional program of fibroblasts in pancreatic cancer and switches on their protumorigenic functions. Proc Natl Acad Sci U S A. 2021; 118: e2020395118.

[10] McAllister F, Bailey JM, Alsina J, et al. Oncogenic Kras activates a hematopoietic-to-epithelial IL-17 signaling axis in preinvasive pancreatic neoplasia. Cancer Cell. 2014; 25: 621-637.

[11] Wu L, Chen X, Zhao J, et al. A novel IL-17 signaling pathway controlling keratinocyte proliferation and tumorigenesis via the TRAF4–ERK5 axis. J Exp Med. 2015; 212: 1571-1587.

[12] Zhang Y, Zoltan M, Riquelme E, et al. Immune Cell production of interleukin 17 induces stem cell features of pancreatic intraepithelial neoplasia cells. Gastroenterology. 2018; 155: 210-223.

[13] Cappello P, Principe M, Bulfamante S, et al. Alpha-enolase (ENO1), a potential target in novel immunotherapies. FBL. 2017; 22: 944-959.

[14] Cappello P, Rolla S, Chiarle R, et al. Vaccination with ENO1 DNA prolongs survival of genetically engineered mice with pancreatic cancer. Gastroenterology. 2013; 144: 1098-1106.

[15] Mandili G, Curcio C, Bulfamante S, et al. In pancreatic cancer, chemotherapy increases antitumor responses to tumor-associated antigens and potentiates DNA vaccination. J Immunother Cancer. 2020; 8: e001071.

[16] Elosua-Bayes M, Nieto P, Mereu E, et al. SPOTlight: seeded NMF regression to deconvolute spatial transcriptomics spots with single-cell transcriptomes. Nucleic Acids Res. 2021; 49: e50.

[17] Candiello E, Reato G, Verginelli F, et al. MicroRNA 483-3p overexpression unleashes invasive growth of metastatic colorectal cancer via NDRG1 downregulation and ensuing activation of the ERBB3/AKT axis. Mol. Oncol. 2023(7): 1280-1301.

[18] Schaum N, Karkanias J, Neff NF, May AP, Quake SR, Wyss-Coray T, et al. Single-cell transcriptomics of 20 mouse organs creates a Tabula Muris. Nature. 2018; 562(7727): 367-372.

[19] Mantovani A, Marchesi F, Malesci A, et al. Tumour-associated macrophages as treatment targets in oncology. Nat Rev Clin Oncol. 2017; 14: 399-416.

[20] Takemoto N, Intlekofer AM, Northrup JT, et al. Cutting Edge: IL-12 inversely regulates T-bet and eomesodermin expression during pathogen-induced CD8+ T cell differentiation. J Immunol. 2006; 177: 7515-7519.

[21] Feig C, Gopinathan A, Neesse A, et al. The pancreas cancer microenvironment. Clin Cancer Res. 2012; 18: 4266-4276.

[22] Liu Y, Du L. Role of pancreatic stellate cells and periostin in pancreatic cancer progression. Tumor Biol. 2015; 36: 3171-3177.

[23] Oelkrug C, Ramage JM. Enhancement of T cell recruitment and infiltration into tumours. Clin Exp Immunol. 2014; 178: 1-8.

[24] Harlin H, Meng Y, Peterson AC, et al. Chemokine expression in melanoma metastases associated with CD8+ T-cell recruitment. Cancer Res. 2009; 69: 3077-3085.

[25] Sauty A, Colvin RA, Wagner L, et al. CXCR3 internalization following T cell-endothelial cell contact: preferential role of IFN-inducible T cell α chemoattractant (CXCL11)1. J Immun. 2001; 167: 7084-7093.

[26] Li N, Mirzakhani H, Kiefer A, et al. Regulated on activation, normal T cell expressed and secreted (RANTES) drives the resolution of allergic asthma. iScience. 2021; 24: 103163.

[27] Saxena M, van der Burg SH, Melief CJM, et al. Therapeutic cancer vaccines. Nat Rev Cancer. 2021; 21: 360-378.

[28] Rojas LA, Sethna Z, Soares KC, et al. Personalized RNA neoantigen vaccines stimulate T cells in pancreatic cancer. Nature. 2023; 618: 144-150.

[29] Heumann T, Judkins C, Li K, et al. A platform trial of neoadjuvant and adjuvant antitumor vaccination alone or in combination with PD-1 antagonist and CD137 agonist antibodies in patients with resectable pancreatic adenocarcinoma. Nat Commun. 2023; 14: 3650.

[30] Whatcott CJ, Diep CH, Jiang P, et al. Desmoplasia in primary tumors and metastatic lesions of pancreatic cancer. Clin Cancer Res. 2015; 21: 3561-3568.

[31] Capello M, Ferri-Borgogno S, Riganti C, et al. Targeting the Warburg effect in cancer cells through ENO1 knockdown rescues oxidative phosphorylation and induces growth arrest. Oncotarget. 2015; 7: 5598-5612.

[32] Principe M, Ceruti P, Shih N-Y, et al. Targeting of surface alpha-enolase inhibits the invasiveness of pancreatic cancer cells. Oncotarget. 2015; 6: 11098-11113.

[33] Principe M, Borgoni S, Cascione M, et al. Alpha-enolase (ENO1) controls alpha v/beta 3 integrin expression and regulates pancreatic cancer adhesion, invasion, and metastasis. J Hematol Oncol. 2017; 10: 16.

[34] Tomaino B, Cappello P, Capello M, et al. Circulating autoantibodies to phosphorylated α-enolase are a hallmark of pancreatic cancer. J Proteome Res. 2011; 10: 105-112.

[35] Cappello P, Tomaino B, Chiarle R, et al. An integrated humoral and cellular response is elicited in pancreatic cancer by alpha-enolase, a novel pancreatic ductal adenocarcinoma-associated antigen. Int J Cancer. 2009; 125: 639-648.

[36] Cappello P, Novelli F. A self antigen reopens the games in pancreatic cancer. Oncoimmunology. 2013; 2: e24384.

[37] Roux C, Mucciolo G, Kopecka J, et al. IL17A depletion affects the metabolism of macrophages treated with gemcitabine. Antioxidants. 2021; 10: 422.

[38] Zhang Y, Chandra V, Riquelme Sanchez E, et al. Interleukin-17–induced neutrophil extracellular traps mediate resistance to checkpoint blockade in pancreatic cancer. J Exp Med. 2020; 217: e20190354.

[39] Picard FSR, Lutz V, Brichkina A, et al. IL-17A-producing CD8 + T cells promote PDAC via induction of inflammatory cancer-associated fibroblasts. Gut. 2023; 72: 1510-1522.

[40] Shiao SL, Kershaw KM, Limon JJ, et al. Commensal bacteria and fungi differentially regulate tumor responses to radiation therapy. Cancer Cell. 2021; 39: 1202-1213.

[41] Aykut B, Pushalkar S, Chen R, et al. The fungal mycobiome promotes pancreatic oncogenesis via activation of MBL. Nature. 2019; 574: 264-267.

[42] Alam A, Levanduski E, Denz P, et al. Fungal mycobiome drives IL-33 secretion and type 2 immunity in pancreatic cancer. Cancer Cell. 2022; 40: 153-167.

[43] Miksch RC, Schoenberg MB, Weniger M, et al. Prognostic impact of tumor-infiltrating lymphocytes and neutrophils on survival of patients with upfront resection of pancreatic cancer. Cancers (Basel). 2019; 11: 39.

[44] Tosello Boari J, Araujo Furlan CL, Fiocca Vernengo F, et al. IL-17RA-signaling modulates CD8+ T cell survival and exhaustion during Trypanosoma cruzi infection. Front Immunol. 2018; 9: 2347.

[45] Hasbold J, Hong JS, Kehry MR, et al. Integrating signals from IFN-gamma and IL-4 by B cells: positive and negative effects on CD40 ligand-induced proliferation, survival, and division-linked isotype switching to IgG1, IgE, and IgG2a. J Immunol. 1999; 163: 4175-4181.

[46] Foote J. Abstract 1342: evaluating the role of antibody in pancreatic tumorigenesis. Cancer Res. 2022; 82: 1342.

[47] Castino GF, Cortese N, Capretti G, et al. Spatial distribution of B cells predicts prognosis in human pancreatic adenocarcinoma. Oncolmmunology. 2016; 5: e1085147.

[48] Das S, Bar-Sagi D. BTK signaling drives CD1dhiCD5+ regulatory B-cell differentiation to promote pancreatic carcinogenesis. Oncogene. 2019; 38: 3316-3324.

[49] Curcio C, Mucciolo G, Roux C, et al. PI3Kγ inhibition combined with DNA vaccination unleashes a B-cell-dependent antitumor immunity that hampers pancreatic cancer. J Exp Clin Cancer Res. 2024; 43: 157.

RIGHTS & PERMISSIONS

2025 The Author(s). Clinical and Translational Medicine published by John Wiley & Sons Australia, Ltd on behalf of Shanghai Institute of Clinical Bioinformatics.