Concurrent Chemoradiotherapy Increases the Levels of Soluble Immune Checkpoint Proteins in Patients with Locally Advanced Cervical Cancer

Abstract

Purpose. Concurrent chemoradiotherapy (CCRT) has been widely applied to locally advanced cervical cancer (LACC) patients, inducing the massive release of antigen and systematic immunomodulatory effects. However, its effect on the soluble immune checkpoint proteins (sICPs) remains unclear, which might play a key role in the immune response. Therefore, the current study explored changes in the levels of 16 sICPs in LACC patients during CCRT. Methods. We prospectively enrolled fifty-one LACC patients treated with CCRT and collected patients’ blood before, during and after CCRT. The levels of 16 sICPs were measured using the Luminex platform, and the changes were measured using Friedman test with Bonferroni’s posttest. One month after CCRT, the tumor response was evaluated according to the RECIST 1.1 guidelines. Results. The levels of soluble T-cell immunoglobulin and mucin-domain containing-3 (sTIM-3) significantly increased during CCRT ( $P=0.041$ ), while those of the soluble B and T lymphocyte attenuator (sBTLA), sCD40, soluble glucocorticoid-induced tumor necrosis factor receptor ligand (sGITRL), sCD80, sCD86, sPD-1, sPD-L1, sCTLA-4, and soluble inducible T-cell costimulator (sICOS) significantly increased after CCRT (all $P<0.05$ ). Other sICPs showed no significant changes throughout the CCRT (all $P>0.05$ ). 41 (80%), 8 (16%), and 2 (4%) patients showed complete response (CR), partial response (PR), and stable disease (SD) after CCRT, respectively. Interestingly, the level of soluble lymphocyte-activation gene 3 (sLAG-3) was significantly higher among the PR/SD patients as compared to the CR after CCRT ( $P=0.009$ ). Conclusions. This study revealed that CCRT might elevate the serum levels of sTIM-3, sBTLA, sCD40, sGITRL, sCD80, sCD86, sPD-1, sPD-L1, sCTLA-4, and sICOS in the patients with LACC. The sLAG-3 level was higher in the patients with poor response to CCRT. These findings revealed the dynamic changes in the sICPs levels during CCRT, which might be helpful in designing optimal treatment strategies for LACC patients.