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Prognostic implications of tumor-infiltrating T cells in early-stage endometrial cancer

Abstract

Patients with endometrial cancer differ in terms of the extent of T-cell infiltration; however, the association between T-cell subpopulations and patient outcomes remains unexplored. We characterized 285 early-stage endometrial carcinoma samples for T-cell infiltrates in a tissue microarray format using multiplex fluorescent immunohistochemistry. The proportion of T cells and their subpopulations were associated with clinicopathological features and relapse-free survival outcomes. CD3+ CD4+ infiltrates were more abundant in the patients with higher grade or non-endometrioid histology. Cytotoxic T cells (CD25+, PD-1+, and PD-L1+) were strongly associated with longer relapse-free survival. Moreover, CD3+ PD-1+ stromal cells were independent of other immune T-cell populations and clinicopathological factors in predicting relapses. Patients with high stromal T-cell fraction of CD3+ PD-1+ cells were associated with a 5-year relapse-free survival rate of 93.7% compared to 79.0% in patients with low CD3+ PD-1+ fraction. Moreover, in patients classically linked to a favorable outcome (such as endometrioid subtype and low-grade tumors), the stromal CD3+ PD-1+ T-cell fraction remained prognostically significant. This study supports that T-cell infiltrates play a significant prognostic role in early-stage endometrial carcinoma. Specifically, CD3+ PD-1+ stromal cells emerge as a promising novel prognostic biomarker.

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Fig. 1: Multiplexed fluorescence IHC (mfIHC).
Fig. 2: Distribution of T cells and their subtypes in patient groups defined by pathological and molecular characteristics.
Fig. 3: T-cell association with disease progression.
Fig. 4: A high number of CD3+ PD-1+ cells predicts favorable outcomes.
Fig. 5: Stromal CD3+ PD-1+/CD3+ cell fraction is an independent prognostic marker.

Data availability

The datasets are available from the corresponding authors upon request.

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Acknowledgements

The authors would like to thank the IdiPAZ biobank core facility for essential services support, as well as the FIMM Digital microscopy and Molecular Pathology Unit supported by HiLIFE and Biocenter Finland for the scanning.

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Authors

Contributions

These are the main contributions by authors: Conceptualization and resources—M.M., T.P., A.R. Data curation—M.M., T.P., J.R.P., A.B., O.B., V.H.S., R.T., J.E., A.H., L.G.C., R.C., A.G., A.H. Software and visualization—T.P., O.B., R.T., A.H. Methodology and Formal analysis—M.M., T.P., J.R.P., A.B., O.B., V.H.-S., R.T., J.E. Supervision and funding acquisition—M.M., J.F., A.R. Funding acquisition—M.M., J.F., A.R. Writing and editing original draft—M.M., T.P., A.R. All authors read, reviewed and approved the final paper.

Corresponding authors

Correspondence to Marta Mendiola or Andres Redondo.

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Competing interests

M.M. reports having received honoraria (MSD, AstraZeneca and GSK), research grant/funding to her institution (Eisai and PharmaMar), and travel/accommodation/expenses (AstraZeneca, GSK, PharmaMar, Roche and Pfizer) outside the submitted work. O.B. reports having received honoraria (Novartis, Sanofi) outside the submitted work. A.G. reports having received honoraria (Clovis, MSD, AstraZeneca, GSK, PharmaMar and Roche) and travel/accommodation/expenses (Merck Sharp & Dohme, PharmaMar, Roche, Eisai, Pfizer, Pierre-Fabre and Tesaro-A GSK Company) outside the submitted work. A.R. reports having received honoraria and providing advisory/consultancy services (MSD, AstraZeneca, Roche, GSK, Clovis, PharmaMar, Lilly, Amgen), as well as having received research grant/funding to his institution (Eisai, PharmaMar, Roche), travel/accommodation/expenses (AstraZeneca, Tesaro: A GSK Company, PharmaMar, Roche), and participating in a speakers bureau (MSD, AstraZeneca, Roche, GSK, Clovis, PharmaMar) outside the submitted work. The remaining authors declare no conflicts of interest.

Ethics approval

The study was approved by the local ethics committee (HULP#PI3778) and was conducted in accordance with the ethical standards of the Declaration of Helsinki of the World Medical Association.

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Mendiola, M., Pellinen, T., Ramon-Patino, J.L. et al. Prognostic implications of tumor-infiltrating T cells in early-stage endometrial cancer. Mod Pathol (2021). https://doi.org/10.1038/s41379-021-00930-7

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