Dynamic alterations in PD-1/PD-L1 expression level and immune cell profiles based on radiation response status in mouse tumor model

Abstract

IntroductionBased on the immunologic effects of anti-cancer treatment and their therapeutic implications, we evaluated radiotherapy (RT)-induced dynamic alterations in programmed death-1 (PD-1)/PD ligand-1 (PD-L1) expression profiles.MethodsLocal RT with 2 Gy × 5 or 7.5 Gy × 1 was administered to the CT26 mouse model. Thereafter, tumors were resected and evaluated at the following predefined timepoints according to radiation response status: baseline, early (immediately after RT), middle (beginning of tumor shrinkage), late (stable status with RT effect), and progression (tumor regrowth). PD-1/PD-L1 activity and related immune cell profiles were quantitatively assessed.ResultsRT upregulated PD-L1 expression in tumor cells from the middle to late phase; however, the levels subsequently decreased to levels comparable to baseline in the progression phase. RT with 2 Gy × 5 induced a higher frequency of PD-L1+ myeloid-derived suppressor cells, with a lesser degree of tumor regression, compared to 7.5 Gy. The proportion of PD-1+ and interferon (IFN)-γ+CD8α T cells continued to increase. The frequency of splenic PD-1+CD8+ T cells was markedly elevated, and was sustained longer with 2 Gy × 5. Based on the transcriptomic data, RT stimulated the transcription of immune-related genes, leading to sequentially altered patterns.DiscussionThe dynamic alterations in PD-1/PD-L1 expression level were observed according to the time phases of tumor regression. This study suggests the influence of tumor cell killing and radiation dosing strategy on the tumor immune microenvironment.

Increased human papillomavirus viral load is correlated to higher severity of cervical disease and poorer clinical outcome: A systematic review

“…Due to the dynamic nature of PD‐L1 expression on a variety of tumors, and the responses thereof to a variety of stimuli, 154–156 one may also be interested in the expression products of HPV at a protein or messenger RNA (mRNA) level. However, viral load is not closely correlated to the expression of HPV genes 157 .…”

Mechanistic rationales for combining immunotherapy with radiotherapy

“…This partially accounts for the increased level of suppressive immune cells, such as Tregs, within the TIME postradiation (148,149). However, tumor residing CD8 + T cells are more radioresistant than naïve and peripheral CD8 + T cells, which has attributed to IR-induced upregulation of TGFb within the TIME (150). This is accompanied by increased CD8 + T cell exhaustion, which is evidenced by increased T eff expression of PD-1 and IFN-g mediated upregulation of tumor PD-L1 expression (151-154).…”