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Supplementary Figure 1 from T-cell Expression of IL10 Is Essential for Tumor Immune Surveillance in the Small Intestine

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posted on 2023-04-03, 23:10 authored by Kristen L. Dennis, Abdulrahman Saadalla, Nichole R. Blatner, Shuya Wang, Vysak Venkateswaran, Fotini Gounari, Hilde Cheroutre, Casey T. Weaver, Axel Roers, Nejat K. Egilmez, Khashayarsha Khazaie

Representative analysis of bone marrow reconstitution efficiency. (A) FACS of total live MNC derived from the intestine of donor CD45.2+ mouse. (B) Frequencies of CD45.1+ and CD45.2+ cells in the intestine of a representative chimeric mouse. CD45.1 donor bone marrow cells were depleted of Lin+ cells and injected into retro-orbital sinus of lethally irradiated 2 month old CD45.2 APCdelta468 mice. To establish the level of bone marrow reconstitution, chimeric APCdelta468 mice were aged to 4 months of age and intestinal MNC were isolated and analyzed by flow cytometry for expression of CD45.2 and CD45.1.

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ARTICLE ABSTRACT

IL10 is attributed with immune-suppressive and anti-inflammatory properties, which could promote or suppress cancer in the gastrointestinal tract. Loss of IL10 exacerbates colonic inflammation, leading to colitis and cancer. Consistent with this, transfer of IL10-competent regulatory T cells (Treg) into mice with colitis or hereditary polyposis protects against disease, while IL10-deficient mice are predisposed to polyposis with increased colon polyp load. Little is known about the protective or pathogenic function of IL10 in cancers of the small intestine. We found CD4+ T cells and CD4+ Foxp3+ Tregs to be the major sources of IL10 in the small intestine and responsible for the increase in IL10 during polyposis in the APCΔ468 mouse model of hereditary polyposis. Targeted ablation of IL10 in T cells caused severe IL10 deficiency and delayed polyp growth. However, these polyps progressively lost cytotoxic activity and eventually progressed to cancer. Several observations suggested that the effect was due to the loss of IFNγ-dependent immune surveillance. IL10-incompetent CD4+ T cells failed to secrete IFNγ when stimulated with polyp antigens and were inefficient in T-helper-1 (TH1) commitment. By contrast, the TH17 commitment was unaffected. These findings were validated using mice whose T cells overexpress IL10. In these mice, we observed high intra-polyp cytotoxic activity and attenuation of polyposis. Thus, expression of IL10 by T cells is protective and required for immune surveillance in the small intestine. Cancer Immunol Res; 3(7); 806–14. ©2015 AACR.