Integration of peripheral blood- and tissue-based biomarkers of response to immune checkpoint blockade in urothelial carcinoma Journal Article
| Authors: | Vanguri, R. S.; Smithy, J. W.; Li, Y.; Zhuang, M.; Maher, C. A.; Aleynick, N.; Peng, X.; Al-Ahmadie, H.; Funt, S. A.; Rosenberg, J. E.; Iyer, G.; Bajorin, D.; Mathews, J. C.; Nadeem, S.; Panageas, K. S.; Shen, R.; Callahan, M. K.; Hollmann, T. J. |
| Article Title: | Integration of peripheral blood- and tissue-based biomarkers of response to immune checkpoint blockade in urothelial carcinoma |
| Abstract: | As predictive biomarkers of response to immune checkpoint inhibitors (ICIs) remain a major unmet clinical need in patients with urothelial carcinoma (UC), we sought to identify tissue-based immune biomarkers of clinical benefit to ICIs using multiplex immunofluorescence and to integrate these findings with previously identified peripheral blood biomarkers of response. Fifty-five pretreatment and 12 paired on-treatment UC specimens were identified from patients treated with nivolumab with or without ipilimumab. Whole tissue sections were stained with a 12-plex mIF panel, including CD8, PD-1/CD279, PD-L1/CD274, CD68, CD3, CD4, FoxP3, TCF1/7, Ki67, LAG-3, MHC-II/HLA-DR, and pancytokeratin+SOX10 to identify over three million cells. Immune tissue densities were compared to progression-free survival (PFS) and best overall response (BOR) by RECIST version 1.1. Correlation coefficients were calculated between tissue-based and circulating immune populations. The frequency of intratumoral CD3+LAG-3+ cells was higher in responders compared to nonresponders (p = 0.0001). LAG-3+ cellular aggregates were associated with response, including CD3+LAG-3+ in proximity to CD3+ (p = 0.01). Exploratory multivariate modeling showed an association between intratumoral CD3+LAG-3+ cells and improved PFS independent of prognostic clinical factors (log HR −7.0; 95% confidence interval [CI] −12.7 to −1.4), as well as established biomarkers predictive of ICI response (log HR −5.0; 95% CI −9.8 to −0.2). Intratumoral LAG-3+ immune cell populations warrant further study as a predictive biomarker of clinical benefit to ICIs. Differences in LAG-3+ lymphocyte populations across the intratumoral and peripheral compartments may provide complementary information that could inform the future development of multimodal composite biomarkers of ICI response. © 2023 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland. © 2023 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland. |
| Keywords: | controlled study; human tissue; treatment response; human cell; major clinical study; flow cytometry; cd3 antigen; cd8 antigen; ki 67 antigen; biomarkers; biological marker; ipilimumab; cancer immunotherapy; progression free survival; cohort analysis; cell population; tissue section; immunotherapy; urothelial carcinoma; cd4 antigen; transitional cell carcinoma; immunocompetent cell; lag-3; programmed death 1 receptor; clinical trial (topic); lymphocyte subpopulation; lymphocyte activation gene 3 protein; overall response rate; checkpoint blockade; immune checkpoint inhibitor; cancer prognosis; nivolumab; human; article; multiplex immunofluorescence; multimodal integration |
| Journal Title: | Journal of Pathology |
| Volume: | 261 |
| Issue: | 3 |
| ISSN: | 0022-3417 |
| Publisher: | Wiley Blackwell |
| Date Published: | 2023-11-01 |
| Start Page: | 349 |
| End Page: | 360 |
| Language: | English |
| DOI: | 10.1002/path.6197 |
| PUBMED: | 37667855 |
| PROVIDER: | scopus |
| PMCID: | PMC11157502 |
| DOI/URL: | |
| Notes: | Article -- MSK Cancer Center Support Grant (P30 CA008748) acknowledged in PubMed -- Source: Scopus |
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