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Programmed death-ligand 1 expression in the immune compartment of colon carcinoma

Abstract

Programmed cell death ligand 1 (PD-L1) on tumor cells is a significant prognostic biomarker for a number of malignancies, although less is known about the significance of PD-L1 positive immune cells in colon carcinoma. The purpose of this study is to evaluate the role of PD-L1 in a large cohort of colon carcinomas to identify patterns of PD-L1 expression in the tumor microenvironment and its correlation with other key immune subsets to better understand the impact of these immune cells. We assessed 1218 colon carcinomas on representative tissue microarray sections, gathered relevant clinicopathologic information, and performed immunohistochemical staining for mismatch repair proteins, CD8, CD163, LAG3, PD-L1, FoxP3, and BRAF V600E. We then performed automated quantification; manual quantification was used for PD-L1 tumor cells and immune cells. Dual PD-L1/PU.1 immunostain was also performed. The majority of PD-L1 positive cells expressed PU.1 thus representing tumor-associated macrophages. Based on the median number of PD-L1 positive immune cells (7.6/mm2), we classified tumors into two classes: (1) PD-L1 immune cell low and (2) PD-L1 immune cell high. PD-L1 immune cell high colon carcinomas showed favorable prognostic pathologic features including less frequent extramural venous invasion (p = 0.0001) and lower AJCC stage (p = 0.0001); they were also more commonly associated with deficient mismatch repair (dMMR) (p = 0.0001) and BRAF V600E reactivity. PD-LI immune cell high tumors were associated with high CD8, CD163, and FoxP3 positive cells (p = 0.0001, respectively). PD-L1 immune cell high and LAG3 high colon carcinomas were associated with improved disease-specific survival (p = 0.0001 and 0.001, respectively). PD-L1 expression on tumor cells was not associated with disease-specific survival. On multivariate analysis of chemotherapy naïve stage 2 colon carcinomas, only extramural venous invasion (p = 0.002), perineural invasion (p = 0.001) and PD-L1 immune cell expression (p = 0.032) correlated with disease-specific survival. Resected colonic carcinomas with high expression of PD-L1 and LAG3 proteins on immune cells were associated with improved prognosis in colon carcinoma. The mechanism underlying the improved prognosis of colon carcinomas bearing high numbers of immunoregulatory cells needs further investigation.

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Fig. 1: Morphologic and immunohistochemical aspects of PD-L1.
Fig. 2: Utility of PU.1 and PD-L1 dual stain.
Fig. 3: Kaplan Meier curve for disease specific survival in relation to PD-L1.
Fig. 4: Immunohistochemical aspects including density and distribution of PD-L1.
Fig. 5: Immune cell and regulatory protein expression in PD-L1 immune high tumors.
Fig. 6: Immune cell and regulatory protein expression in PD-L1 immune low tumors.
Fig. 7: Kaplan-Meier curve for disease specific survival in relation to LAG3.

Data availability

The data that support the findings of this study are not openly available to maintain patient confidentiality but de-identified data are available from the corresponding author upon reasonable request.

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Funding

Vikram Deshpande is partially funded by NIH grant.

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Contributions

Contributed to collection of material, planning and performing experiments and analysis of data: AN, AP, AC, LL, AD, MT, SGS, RC, MLZ, OHY, SR. Conceived and planned the experiments: VD, DTT, DB, SC, QZ, MT, SGS, RC, MLZ, OY, DP. Conceived the study and in charge of overall direction and planning: VD. Wrote the paper with input from all authors: AN, AP, AC, LL, AD, MT, SGS, RC, MLZ, OHY, SR, ERL, QZ, SC, OHY, OY, CF, DTP, DTT, DB, VD. All authors discussed the results and contributed to the final manuscript.

Corresponding author

Correspondence to Vikram Deshpande.

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Competing interests

DTT has received consulting fees from ROME Therapeutics, Tekla Capital, Ikena Oncology, Foundation Medicine, Inc., NanoString Technologies, EMD Millipore Sigma, and Pfizer that are not related to this work. DTT is a founder and has equity in ROME Therapeutics, PanTher Therapeutics, and TellBio, Inc., which is not related to this work. DTT receives research support from ACD-Biotechne, PureTech Health LLC, and Ribon Therapeutics, which was not used in this work. DTT’s interests were reviewed and are managed by Massachusetts General Hospital and Mass General Brigham in accordance with their conflict of interest policies. The other authors do not have any relevant disclosures.

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The study was approved by MGB IRB number 2017P61.

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Yılmaz, O., Pankaj, A., Neyez, A. et al. Programmed death-ligand 1 expression in the immune compartment of colon carcinoma. Mod Pathol (2022). https://doi.org/10.1038/s41379-022-01128-1

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