Blockade of interleukin 10 potentiates antitumour immune function in human colorectal cancer liver metastases. Issue 2 (15th June 2022)

• Record Type: Journal Article
• Authors: Sullivan, Kevin M; Jiang, Xiuyun; Guha, Prajna; Lausted, Christopher; Carter, Jason A; Hsu, Cynthia; Labadie, Kevin P; Kohli, Karan; Kenerson, Heidi L; Daniel, Sara K; Yan, Xiaowei; Meng, Changting; Abbasi, Arezou; Chan, Marina; Seo, Y David; Park, James O; Crispe, Ian Nicholas; Yeung, Raymond S; Kim, Teresa S; Gujral, Taranjit S; Tian, Qiang; Katz, Steven C; Pillarisetty, Venu G
• Is Part Of: Gut. Volume 72:Issue 2(2023)
• Page Start: 325
• Page End: 337
• Publication Date: 2022-06-15
• Subjects: IMMUNOLOGY -- COLORECTAL METASTASES -- INTERLEUKINS -- IMMUNOTHERAPY -- LIVER METASTASES; Gastroenterology -- Periodicals; 616.33
• DOI: 10.1136/gutjnl-2021-325808
• Languages: English
• ISSNs: 0017-5749

Abstract

Abstract : Objective: Programmed cell death protein 1 (PD-1) checkpoint inhibition and adoptive cellular therapy have had limited success in patients with microsatellite stable colorectal cancer liver metastases (CRLM). We sought to evaluate the effect of interleukin 10 (IL-10) blockade on endogenous T cell and chimeric antigen receptor T (CAR-T) cell antitumour function in CRLM slice cultures. Design: We created organotypic slice cultures from human CRLM (n=38 patients' tumours) and tested the antitumour effects of a neutralising antibody against IL-10 (αIL-10) both alone as treatment and in combination with exogenously administered carcinoembryonic antigen (CEA)-specific CAR-T cells. We evaluated slice cultures with single and multiplex immunohistochemistry, in situ hybridisation, single-cell RNA sequencing, reverse-phase protein arrays and time-lapse fluorescent microscopy. Results: αIL-10 generated a 1.8-fold increase in T cell-mediated carcinoma cell death in human CRLM slice cultures. αIL-10 significantly increased proportions of CD8 + T cells without exhaustion transcription changes, and increased human leukocyte antigen - DR isotype (HLA-DR) expression of macrophages. The antitumour effects of αIL-10 were reversed by major histocompatibility complex class I or II (MHC-I or MHC-II) blockade, confirming the essential role of antigen presenting cells. Interrupting IL-10 signalling also rescued murine CAR-T cell proliferation and cytotoxicity from myeloid cell-mediated immunosuppression. In human CRLM slices, αIL-10 increased CEA-specific CAR-T cell activation and CAR-T cell-mediated cytotoxicity, with nearly 70% carcinoma cell apoptosis across multiple human tumours. Pretreatment with an IL-10 receptor blocking antibody also potentiated CAR-T function. Conclusion: Neutralising the effects of IL-10 in human CRLM has therapeutic potential as a stand-alone treatment and to augment the function of adoptively transferred CAR-T cells.