High density of cytotoxic T-lymphocytes is linked to tumoral PD-L1 expression regardless of the mismatch repair status in colorectal cancer.

Abstract

BACKGROUND:

Immune checkpoint-inhibitors targeting the PD-1/PD-L1 system are FDA approved in microsatellite instable (MSI) or mismatch repair deficient (dMMR) colorectal cancer (CRC). PD-L1 expression is tightly linked to features connected to immune checkpoint inhibitor response, but studies on large subsets of cancers analyzing the correlation between different status of MSI/dMMR, tumor infiltrating lymphocytes and PD-L1 expression are still lacking.

METHODS:

More than 1800 CRC were analyzed for PD-L1 by immunohistochemistry in a tissue microarray format. Data were compared to MMR, the number of intratumoral CD8+ cytotoxic T-cells, and adverse clinico-pathological parameters. Different cutoff levels for defining PD-L1 positivity in tumor cells (1%, 5%, 10%, and 50%) yielded comparable results.

RESULTS:

At a cutoff level of 5%, PD-L1 positivity was seen in 5.1% of tumors. PD-L1 was more often positive in dMMR (18.6%) than in MMR proficient (pMMR) cancers (4.1%; p < 0.0001). The number of intratumoral CD8+ lymphocytes was strikingly higher in PD-L1 positive (939.5 ± 118.2) than in PD-L1 negative cancers (310.5 ± 24.8). A higher number of intratumoral CD8+ lymphocytes was found in dMMR CRC (PD-L1 positive: 1999.7 ± 322.0; PD-L1 negative: 398.6 ± 128.0; p < 0.0001) compared to pMMR CRC (PD-L1 positive: 793.2 ± 124.8; PD-L1 negative: 297.2 ± 24.2; p < 0.0001). In dMMR and pMMR CRC, PD-L1 expression in tumor cells was unrelated to tumor stage, lymph node status or lymphatic/venous invasion. PD-L1 positivity in tumor associated immune cells was seen in 47.5% of cases and was significantly linked to high numbers of tumor infiltrating CD8+, low tumor stage, and absence of lymph node metastasis and lymphatic/venous invasion (p < 0.0001 each).

CONCLUSION:

The data support the previously suggested fact that PD-L1 expression in tumor cells is driven by extensive cytotoxic T-cell infiltration in highly immunogenic dMMR and pMMR CRC. Frequent and intense PD-L1 expression in tumor cells of dMMR CRC may contribute to the high response rates of dMMR CRC to immune checkpoint-inhibitors.

• Authors: Katharina Möller, Niclas C Blessin, Doris Höflmayer, Franziska Büscheck, Andreas M Luebke, Martina Kluth, Claudia Hube-Magg, Katarzyna Zalewski, Andrea Hinsch, Michael Neipp, Hamid Mofid, Hannes Lárusson, Thies Daniels, Christoph Isbert, Stephan Coerper, Daniel Ditterich, Holger Rupprecht, Albert Goetz, Christian Bernreuther, Guido Sauter, Ria Uhlig, Waldemar Wilczak, Ronald Simon, Stefan Steurer, Sarah Minner, Eike Burandt, Till Krech, Daniel Perez, Jakob R Izbicki, Till S Clauditz, Andreas H Marx
• Journal: Acta oncologica (Stockholm, Sweden) (Acta Oncol) Vol. 60 Issue 9 Pg. 1210-1217 (Sep 2021) ISSN: 1651-226X [Electronic] England
• PMID: 34092167 (Publication Type: Journal Article)

Chemical References

• B7-H1 Antigen

Topics

• B7-H1 Antigen (genetics)
• Colorectal Neoplasms (genetics)
• DNA Mismatch Repair (genetics)
• Humans
• Microsatellite Instability
• T-Lymphocytes, Cytotoxic