Micro Immune Response On-chip (MIRO) models the tumour-stroma interface for immunotherapy testing

Abstract

Immunotherapies are beneficial for a considerable proportion of cancer patients, but ineffective in others. In vitro modelling of the complex interactions between cancer cells and their microenvironment could provide a path to understanding immune therapy sensitivity and resistance. Here we develop MIRO, a fully humanised in vitro platform to model the spatial organisation of the tumour/stroma interface and its interaction with immune cells. We find that stromal barriers are associated with immune exclusion and protect cancer cells from antibody-dependent cellular cytotoxicity, elicited by targeted therapy. We demonstrate that IL2-driven immunomodulation increases immune cell velocity and spreading to overcome stromal immunosuppression and restores anti-cancer response in refractory tumours. Collectively, our study underscores the translational value of MIRO as a powerful tool for exploring how the spatial organisation of the tumour microenvironment shapes the immune landscape and influences the responses to immunomodulating therapies.

We thank S. Usieto, S. Menendez Romero, D. Zafra Puerta, A. Menendez, D. Izquierdo Garcia, C. Rols, J. Durand for their technical assistance. A.L. acknowledges funding from “La Caixa” Banking Foundation (LCF/BQ/PR18/11640001) and from the Spanish Ministry for Science and Innovation MICIU/AEI /10.13039/501100011033 and “ERDF-EU A way of making Europe”, (PID2021-128635NB-I00), and “ESF Investing in your future”, (RYC2020/029736/I). This work was also supported by grants from Instituto de Salud Carlos III (ISCIII) co-funded by the European Union (EU) (PI17/00211, CP16/00151, PI20/00011; Spanish Ministry of Economy and Competitiveness) to A.C. A.C. is the recipient of Miguel Servet research contracts from Instituto de Salud Carlos III co-funded by the European Union (MS16/00151, CPII21/00012). J.A. acknowledges funding from the Generalitat de Catalunya (AGAUR 2021 SGR 00776), the CIBERONC (CB16/12/00241), and the ISCIII co-funded by the EU (PI21/00002). This work was also supported by the Plan de Recuperación, Transformación y Resiliencia (CNS2023-145267) co-funded by the European Union to A.C. P.R.-C. acknowledges funding from the Spanish Ministry of Science and Innovation (PID2022-142672NB-I00), the European Research Council (AdG 101097753), the Generalitat de Catalunya (2017-SGR-1602), and the prize ‘ICREA Academia’ for excellence in research. X.T. acknowledges funding from the Generalitat de Catalunya (AGAUR SGR-2017-01602), the CERCA Programme, the Spanish Ministry for Science and Innovation MICCINN/FEDER (PID2021-128635NB-I00 MCIN/AEI/ 10.13039/501100011033 and “ERDF-EU A way of making Europe”), European Research Council (Adv-883739), Fundació la Marató de TV3 (project 201903-30-31-32), European Commission (H2020-FETPROACT-01-2016-731957), La Caixa Foundation (LCF/PR/HR20/52400004 and ID 100010434 under the agreement LCF/PR/HR20/52400004); IBEC and IRB are recipient of a Severo Ochoa Award of Excellence from the MINECO. This work was also supported by Grant PT20/00023, funded by Instituto de Salud Carlos III (ISCIII) and co-funded by the European Union, and the “Xarxa de Bancs de tumors” sponsored by Pla Director d’Oncologia de Catalunya (XBTC).