Abstract B079: Interleukin-33 activated ILC2s induce tertiary lymphoid structures in pancreatic cancer

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Abstract Background: Tertiary lymphoid structures (TLS) are ectopic immune cell aggregates in tumors that correlate with enhanced immunity and prognosis. Although TLS form via lymphotoxin (LT)-LTβR signaling, the TLS inducing molecules and cells remain unclear. Approach: To identify TLS inducing signals, we use pancreatic ductal adenocarcinoma (PDAC), a cold tumor where increased TLS density correlates with enhanced survival. To discover novel TLS inducers, we analyze bulk transcriptomes from human PDAC and 12 cold and hot cancers. We dissect the mechanisms in a Kras/p53-driven orthotopic PDAC mouse model, parabiosis, and inducible cell tracing. Results: In 328 analyzed human PDAC transcriptomes, we discover IL33–the alarmin released in inflamed tissues– among the most strongly correlated molecules with three distinct TLS signatures in PDAC (P<0.001) and 3887 human tumors (P<0.001). To test if this correlation is causative, we found anti-LTβR agonism induced intratumoral TLS density in wild-type but not Il33 -/- PDAC mice (P<0.001). To probe if IL33 served as an extracellular TLS trigger, we found recombinant IL33 (rIL33) boosted intratumoral TLS by up to 10-fold across six PDAC cell lines (P≤0.01–0.001) and reduced tumor growth. Thus, IL33 is a novel TLS-inducing alarmin. To identify the TLS inducer cells, we found that rIL33 dominantly expands intratumoral type 2 Innate Lymphoid cells (ILC2) expressing LT, suggesting ILC2 as TLS inducers. To test if ILC2 contribute to IL33-mediated TLS, we acutely depleted ILC2 using Nmur1 iCre-eGFP ROSA26 LSL-DTR mice and observed a ∼65% reduction in TLS during rIL33 treatment (P=0.006). Consistently, conditional LT depletion on ILC2 using Nmur1 iCre-eGFP Ltb fl/fl mice reduces TLS by ∼70% (P=0.006). Thus, IL33-activated ILC2s induce TLSs via LT. As rIL33 expands blood ILC2, we examined if ILC2 migrated to tumors. In parabiotic mice with PDACs in recipient pancreata, rIL33 treatment in donor mice induced hematogenous ILC2 migration to recipient PDACs (P=0.02). To trace the origin of intratumoral ILC2, we used photoconvertible KikGR mice. In rIL33-treated PDAC mice, we detected photoconverted ILC2 in tumors of gut-photoconverted but not control mice (P<0.001), demonstrating that ILC2 can migrate to PDACs through a gut-blood circuit. Furthermore, PDAC increases intrapancreatic ILC2 frequencies (P<0.001) and alters microbiota composition. Antibiotic-mediated depletion of the microbiota reduces blood ILC2 frequencies (P=0.01) and intratumoral TLS (P=0.02), suggesting that gut microbiota may regulate ILC2 migration to tumors. Finally, to exploit this lymphoneogenic pathway for immunotherapy, we demonstrated that engineered recombinant human IL33 expands intratumoral ILC2, TLS, and enhances anti-tumor activity in PDAC mice. Conclusions: In summary, we identify IL33 and ILC2 as novel molecule and cells that induce TLS in pancreatic cancer. As PDAC is a model cold cancer resistant to current immunotherapies, our findings position rIL33 as a promising immunotherapy to enhance TLS formation to treat cancer. Citation Format: Abderezak Zebboudj, Masataka Amisaki, Hiroshi Yano, Siqi Linsey Zhang, George Payne, Adrienne Kaya Chandra, Rebecca Yu, Pablo Guasp, Zachary M Sethna, Akihiro Ohmoto, Luis A. Rojas, Charlotte Cheng, Theresa Waters, Alexander Solovyov, Stephen Martis, Ashley Doane, Charlotte Reiche, Emmanuel Bruno, Martina Milighetti, Kevin Soares, Zagaa Odgerel, John Alec Moral, Julia Zaho, Mithat Gönen, Rui Gardner, Alexei V Tumanov, Abdul G Khan, Olivia Vergnolle, Elisabeth Nyakatura, Ivo C. Lorenz, Manuel Baca, Erin Patterson, Benjamin Greenbaum, David Artis, Taha Merghoub, Vinod P. Balachandran. Interleukin-33 activated ILC2s induce tertiary lymphoid structures in pancreatic cancer [abstract]. In: Proceedings of the AACR IO Conference: Discovery and Innovation in Cancer Immunology: Revolutionizing Treatment through Immunotherapy; 2025 Feb 23-26; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Immunol Res 2025;13(2 Suppl):Abstract nr B079.

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