Blockade of interleukin 10 potentiates antitumour immune function in human colorectal cancer liver metastases.
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
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.
Institute for Systems Biology
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; and Pillarisetty, Venu G, "Blockade of interleukin 10 potentiates antitumour immune function in human colorectal cancer liver metastases." (2022). Articles, Abstracts, and Reports. 6165.