Spatial effects of infiltrating T cells on neighbouring cancer cells and prognosis in stage III CRC patients Journal Article
| Authors: | Azimi, M.; Cho, S.; Bozkurt, E.; McDonough, E.; Kisakol, B.; Matveeva, A.; Salvucci, M.; Dussmann, H.; McDade, S.; Firat, C.; Urganci, N.; Shia, J.; Longley, D. B.; Ginty, F.; Prehn, J. H. M. |
| Article Title: | Spatial effects of infiltrating T cells on neighbouring cancer cells and prognosis in stage III CRC patients |
| Abstract: | Colorectal cancer (CRC) is one of the most frequently occurring cancers, but prognostic biomarkers identifying patients at risk of recurrence are still lacking. In this study, we aimed to investigate in more detail the spatial relationship between intratumoural T cells, cancer cells, and cancer cell hallmarks as prognostic biomarkers in stage III colorectal cancer patients. We conducted multiplexed imaging of 56 protein markers at single-cell resolution on resected fixed tissue from stage III CRC patients who received adjuvant 5-fluorouracil (5FU)-based chemotherapy. Images underwent segmentation for tumour, stroma, and immune cells, and cancer cell ‘state’ protein marker expression was quantified at a cellular level. We developed a Python package for estimation of spatial proximity, nearest neighbour analysis focusing on cancer cell–T-cell interactions at single-cell level. In our discovery cohort (Memorial Sloan Kettering samples), we processed 462 core samples (total number of cells: 1,669,228) from 221 adjuvant 5FU-treated stage III patients. The validation cohort (Huntsville Clearview Cancer Center samples) consisted of 272 samples (total number of cells: 853,398) from 98 stage III CRC patients. While there were trends for an association between the percentage of cytotoxic T cells (across the whole cancer core), it did not reach significance (discovery cohort: p = 0.07; validation cohort: p = 0.19). We next utilised our region-based nearest neighbour approach to determine the spatial relationships between cytotoxic T cells, helper T cells, and cancer cell clusters. In both cohorts, we found that shorter distance between cytotoxic T cells, T helper cells, and cancer cells was significantly associated with increased disease-free survival. An unsupervised trained model that clustered patients based on the median distance between immune cells and cancer cells, as well as protein expression profiles, successfully classified patients into low-risk and high-risk groups (discovery cohort: p = 0.01; validation cohort: p = 0.003). © 2024 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland. © 2024 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland. |
| Keywords: | adult; controlled study; human tissue; protein expression; aged; middle aged; human cell; major clinical study; fluorouracil; disease free survival; chemotherapy, adjuvant; cancer staging; neoplasm staging; colorectal cancer; cd8 antigen; ki 67 antigen; transcription factor foxp3; cd8+ t lymphocyte; t lymphocyte; tumor associated leukocyte; lymphocytes, tumor-infiltrating; metabolism; protein bcl 2; cohort analysis; caspase 3; pathology; tumor marker; colorectal neoplasms; cd20 antigen; immunology; colorectal tumor; colon cancer; adjuvant chemotherapy; microsatellite instability; myc protein; cancer cell; cd4+ t lymphocyte; cytotoxic t lymphocyte; hla antigen class 1; caspase 8; caspase 9; high risk population; cd4 antigen; tissue microarray; lymphocytic infiltration; cell interaction; immunocompetent cell; helper cell; glucose transporter 1; tumor microenvironment; protein bax; spatial analysis; protein bak; fas associated death domain protein; apoptotic protease activating factor 1; x linked inhibitor of apoptosis; low risk patient; immune cells; cancer prognosis; humans; prognosis; human; male; female; article; lactate dehydrogenase a; biomarkers, tumor; multiplex immunofluorescence; nearest neighbour analysis; tumour infiltration; endoplasmic reticulum chaperone bip |
| Journal Title: | Journal of Pathology |
| Volume: | 264 |
| Issue: | 2 |
| ISSN: | 0022-3417 |
| Publisher: | Wiley Blackwell |
| Date Published: | 2024-10-01 |
| Start Page: | 148 |
| End Page: | 159 |
| Language: | English |
| DOI: | 10.1002/path.6327 |
| PUBMED: | 39092716 |
| PROVIDER: | scopus |
| DOI/URL: | |
| Notes: | The MSK Cancer Center Support Grant (P30 CA008748) is acknowledged in the PubMed record and PDF -- Source: Scopus |
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