1312 Gut dysbiosis suppresses anti-tumor ILC2s in pancreatic cancer

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Background Symbiotic microbes that colonize gut promote host immunity.1 Cancer disrupts this homeostasis to alter microbial populations (“dysbiosis”) that suppresses anti-cancer immunity. Yet, the mechanisms of how dysbiosis suppresses anti-tumor immunity remain unclear. Group 2 innate lymphoid cells (ILC2s) are innate lymphocytes that reside in tissues including the gut, respond to the alarmin interleukin-33 (IL-33), and maintain microbial homeostasis in barrier surfaces.2 ILC2s also activate anti-tumor immunity in multiple cancers.3-7 Yet, links between dysbiosis, ILC2s, and anti-tumor immunity, remain unexplored. Methods To investigate if cancer dysbiosis modulates ILC2s, we examined dysbiosis in pancreatic ductal adenocarcinoma (PDAC), where dysbiosis correlates with fewer intratumoral T cells and worse survival.8,9 PDAC is also infiltrated by anti-tumor ILC2s.7 Briefly, we analyzed dysbiosis by 16S-rRNA gene sequencing in fecal samples of PDAC mice deficient or not for ILC2s or IL33. To study the effect of dysbiosis on ILC2s, we ablated dysbiosis using antibiotics or reconstituted it in germ-free mice, we explored ILC2s migration using parabiosis. Results We found that PDAC induced Bacteroidetes overgrowth, thus phenocopying PDAC dysbiosis in patients.8,10,11 Interestingly, PDAC-dysbiosis suppressed intestinal ILC2s frequencies, as dysbiosis ablation with antibiotics increased, and fecal transplantation in germ-free mice conversely decreased intestinal ILC2 frequencies. Reciprocally, we found that ILC2 and IL33-deficient mice evidenced Bacteroidetes overgrowth at steady state, thus phenocopying the PDAC-induced dysbiosis. Interestingly, ILC2 and IL33-deficient mice also evidenced accelerated PDAC growth, and worse survival compared to wild-type mice (WT). Thus, PDAC-dysbiosis suppresses intestinal ILC2s that serve to maintain optimal gut homeostasis. We next investigated how dysbiosis-induced ILC2s suppression modulates tumor growth. We previously reported that IL-33 responsive ILC2s infiltrate PDAC to activate antigen-specific CD8+T cells.7 We identified these anti-tumor ILC2s as unique migratory ILC2s that traffic to tumors. We thus hypothesized dysbiosis may promote tumors by modulating ILC2s migration from the intestine reservoir. Consistently, in parabiotic mice, recombinant IL-33 (rIL-33) induced ILC2s to migrate hematogenously to PDACs in different tissues, and antibiotic ablation of dysbiosis lowered donor-derived ILC2s frequencies in recipient blood and intestine. Thus, dysbiosis modulates anti-tumor ILC2s frequencies in circulation and gut reservoirs. Interestingly, in WT PDAC mice, rIL-33 expanded intestinal ILC2s, restored microbiome composition, increased tumor-infiltrating ILC2s, and reduced PDAC growth. Conclusions We find that cancer dysbiosis suppresses anti-tumor immunity by suppressing gut-derived ILC2s. Moreover, rIL-33 expands ILC2s in the gut and circulation to restore dysbiosis-suppressed ILC2s and controls PDAC. We thus introduce the therapeutic potential of IL33-based immunotherapies to reverse the dysbiotic state in cancer. References Thaiss CA, Zmora N, Levy M, Elinav E. The microbiome and innate immunity. Nature. 2016;535(7610):65–74. Monticelli LA, Osborne LC, Noti M, Tran S V, Zaiss DMW, Artis D. IL-33 promotes an innate immune pathway of intestinal tissue protection dependent on amphiregulin-EGFR interactions. Proc Natl Acad Sci U S A. 2015;112(34):10762–7. Ikutani M, Yanagibashi T, Ogasawara M, Tsuneyama K, Yamamoto S, Hattori Y, et al. Identification of Innate IL-5–Producing Cells and Their Role in Lung Eosinophil Regulation and Antitumor Immunity. J Immunol. 2012 Jan 15;188(2):703–13. Kim J, Kim W, Moon UJ, Kim HJ, Choi H-J, Sin J-I, et al. Intratumorally Establishing Type 2 Innate Lymphoid Cells Blocks Tumor Growth. J Immunol. 2016;196(5):2410–23. Saranchova I, Han J, Zaman R, Arora H, Huang H, Fenninger F, et al. Type 2 innate lymphocytes actuate immunity against tumours and limit cancer metastasis. Sci Rep. 2018;8(1). Jacquelot N, Seillet C, Wang M, Pizzolla A, Liao Y, Hediyeh-zadeh S, et al. Blockade of the co-inhibitory molecule PD-1 unleashes ILC2-dependent antitumor immunity in melanoma. Nat Immunol [Internet]. 2021;22(7):851–64. Available from: http://dx.doi.org/10.1038/s41590-021-00943-z Moral JA, Leung J, Rojas LA, Ruan J, Zhao J, Sethna Z, et al. ILC2s amplify PD-1 blockade by activating tissue-specific cancer immunity. Nature [Internet]. 2020;579(7797):130–5. Available from: http://dx.doi.org/10.1038/s41586-020-2015-4 Riquelme E, Zhang Y, Zhang L, Montiel M, Zoltan M, Dong W, et al. Tumor microbiome diversity and composition influence pancreatic cancer outcomes. Cell [Internet]. 2019;178(4):795-806.e12. Available from: https://doi.org/10.1016/j.cell.2019.07.008 Pushalkar S, Hundeyin M, Daley D, Zambirinis CP, Kurz E, Mishra A, et al. The pancreatic cancer microbiome promotes oncogenesis by induction of innate and adaptive immune suppression. Cancer Discov. 2018;8(4):403–16. Half E, Keren N, Reshef L, Dorfman T, Lachter I, Kluger Y, et al. Fecal microbiome signatures of pancreatic cancer patients. Sci Rep. 2019;9(1):1–12. Ren Z, Jiang J, Xie H, Li A, Lu H, Xu S, et al. Gut microbial profile analysis by MiSeq sequencing of pancreatic carcinoma patients in China. Oncotarget. 2017;8(56):95176–91.

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