Using high-resolution sequencing and immunohistochemistry, Angelova et al. performed a longitudinal analysis on 31 metastases derived from two patients with stage IV colorectal carcinoma with long-term survival. The researchers delineated the evolution of metastases, observed significant heterogeneity between and within metastases, and determined that progression arose from immune-escaping (non-immunogenic or unedited) clones, shaped under immune pressure at different sites. For each individual metastasis, high immunoscore and immunoediting, and smaller tumor size predicted the lowest risk of recurrence.
We examined how the immune microenvironment molds tumor evolution at different metastatic organs in a longitudinal dataset of colorectal cancer. Through multiplexed analyses, we showed that clonal evolution patterns during metastatic progression depend on the immune contexture at the metastatic site. Genetic evidence of neoantigen depletion was observed in the sites with high Immunoscore and spatial proximity between Ki67(+) tumor cells and CD3(+) cells. The immunoedited tumor clones were eliminated and did not recur, while progressing clones were immune privileged, despite the presence of tumor-infiltrating lymphocytes. Characterization of immune-privileged metastases revealed tumor-intrinsic and tumor-extrinsic mechanisms of escape. The lowest recurrence risk was associated with high Immunoscore, occurrence of immunoediting, and low tumor burden. We propose a parallel selection model of metastatic progression, where branched evolution could be traced back to immune-escaping clones. The findings could inform the understanding of cancer dissemination and the development of immunotherapeutics.
Author Info: (1) INSERM, Laboratory of Integrative Cancer Immunology, Sorbonne Universite, Sorbonne Paris Cite, Universite Paris Descartes, Universite Paris Diderot, Centre de Recherche des Cor
Author Info: (1) INSERM, Laboratory of Integrative Cancer Immunology, Sorbonne Universite, Sorbonne Paris Cite, Universite Paris Descartes, Universite Paris Diderot, Centre de Recherche des Cordeliers, 75006 Paris, France. (2) INSERM, Laboratory of Integrative Cancer Immunology, Sorbonne Universite, Sorbonne Paris Cite, Universite Paris Descartes, Universite Paris Diderot, Centre de Recherche des Cordeliers, 75006 Paris, France; Inovarion, Paris, France. (3) INSERM, Laboratory of Integrative Cancer Immunology, Sorbonne Universite, Sorbonne Paris Cite, Universite Paris Descartes, Universite Paris Diderot, Centre de Recherche des Cordeliers, 75006 Paris, France. (4) INSERM, Laboratory of Integrative Cancer Immunology, Sorbonne Universite, Sorbonne Paris Cite, Universite Paris Descartes, Universite Paris Diderot, Centre de Recherche des Cordeliers, 75006 Paris, France. (5) INSERM, Laboratory of Integrative Cancer Immunology, Sorbonne Universite, Sorbonne Paris Cite, Universite Paris Descartes, Universite Paris Diderot, Centre de Recherche des Cordeliers, 75006 Paris, France. (6) INSERM, Laboratory of Integrative Cancer Immunology, Sorbonne Universite, Sorbonne Paris Cite, Universite Paris Descartes, Universite Paris Diderot, Centre de Recherche des Cordeliers, 75006 Paris, France. (7) INSERM, Laboratory of Integrative Cancer Immunology, Sorbonne Universite, Sorbonne Paris Cite, Universite Paris Descartes, Universite Paris Diderot, Centre de Recherche des Cordeliers, 75006 Paris, France. (8) INSERM, Laboratory of Integrative Cancer Immunology, Sorbonne Universite, Sorbonne Paris Cite, Universite Paris Descartes, Universite Paris Diderot, Centre de Recherche des Cordeliers, 75006 Paris, France. (9) INSERM, Laboratory of Integrative Cancer Immunology, Sorbonne Universite, Sorbonne Paris Cite, Universite Paris Descartes, Universite Paris Diderot, Centre de Recherche des Cordeliers, 75006 Paris, France. (10) Institut Roi Albert II, Department of Medical Oncology Cliniques universitaires St-Luc and Institut de Recherche Clinique et Experimentale (Pole MIRO), Universite Catholique de Louvain, 1348 Brussels, Belgium. (11) Institut Roi Albert II, Department of Medical Oncology Cliniques universitaires St-Luc and Institut de Recherche Clinique et Experimentale (Pole MIRO), Universite Catholique de Louvain, 1348 Brussels, Belgium. (12) Institut Roi Albert II, Department of Medical Oncology Cliniques universitaires St-Luc and Institut de Recherche Clinique et Experimentale (Pole MIRO), Universite Catholique de Louvain, 1348 Brussels, Belgium. (13) Institut Roi Albert II, Department of Medical Oncology Cliniques universitaires St-Luc and Institut de Recherche Clinique et Experimentale (Pole MIRO), Universite Catholique de Louvain, 1348 Brussels, Belgium. (14) Department of Science and Technology, Universita degli Studi del Sannio, 82100, Benevento, Italy; BIOGEM Istituto di Ricerche Genetiche "G. Salvatore," I-83031 Ariano Irpino, Italy. (15) Biomedical Informatics Division, Sidra Medicine, Doha, Qatar. (16) Refuge Biotechnologies Inc., Menlo Park, CA 94025, USA; Office of the Chief Research Officer, Sidra Medicine, 26999 Doha, Qatar. (17) Tumor Biology, Immunology, and Therapy Section, Sidra Medicine, 26999 Doha, Qatar. (18) INSERM, Laboratory of Integrative Cancer Immunology, Sorbonne Universite, Sorbonne Paris Cite, Universite Paris Descartes, Universite Paris Diderot, Centre de Recherche des Cordeliers, 75006 Paris, France; Institut Roi Albert II, Department of Medical Oncology Cliniques universitaires St-Luc and Institut de Recherche Clinique et Experimentale (Pole MIRO), Universite Catholique de Louvain, 1348 Brussels, Belgium. (19) INSERM, Laboratory of Integrative Cancer Immunology, Sorbonne Universite, Sorbonne Paris Cite, Universite Paris Descartes, Universite Paris Diderot, Centre de Recherche des Cordeliers, 75006 Paris, France. Electronic address: jerome.galon@crc.jussieu.fr.
