1. Department of Pathology, Harbin Medical University, Harbin, China.
2. Faculty of Health Sciences, University of Macau, Macau, China
3. Department of Gastrointestinal Medical Oncology, the Affiliated Tumor Hospital of Harbin Medical University, Harbin, China.
4. Shuwen Biotech Co. Ltd., Deqing, China.
5. Department of Pathology, People's Hospital of Liaoning Province. Shenyang, China.
6. Department of Medical Oncology, People's Hospital of Liaoning Province. Shenyang, China.
*These authors contributed equally to this work.
The prognostic value of programmed death-ligand 1 (PD-L1) has been controversial in recent studies. PD-L1 is known to play a major role in suppressing the immune response, yet increasing studies have reported that PD-L1 expression has a favorable prognostic value for cancer patients. This raises the concern about how to understand PD-L1 expression: merely an immune inhibitory signal, or more likely a reactive process to T-cell response that indicates cytotoxic T lymphocyte (CTL) level in a tumor? To solve this dilemma, an integrative investigation is required. We compared the PD-L1 expression between tumor cells and immune cells, and characterized the inter- and intra-tumor correlation between CTL and PD-L1 expression. The prognostic values between PD-L1 and CTL is compared across 15 solid cancers and 11 independent cohorts of ovarian cancer. PD-L1 and PD-L1-adjusted CTL are analyzed in immunotherapy dataset receiving nivolumab. We observed unexpected high concordance between the prognostic value of PD-L1 and CTL across different cancers and cohorts. We found primarily reactive rather than constitutive PD-L1 expression in most tumors. We revealed that PD-L1-adjusted CTL level, rather than the expression of PD-L1, effectively predicts the responders to immune checkpoint inhibitors. This study highlights the importance of PD-L1 expression, as primarily a signature of reacting efficiency of pre-existing anti-tumor immunity, in balancing the tumor microenvironment. Importantly, it suggests that the reactive efficiency of PD-L1 is more useful to predict the response to immunotherapy.
Keywords: PD-L1, CTL, cancer, immunotherapy, microenvironment