Soluble immune checkpoints: implications for cancer prognosis and response to immune checkpoint therapy and conventional therapies

Abstract

Longitudinal sampling of tumor tissue from patients with solid cancers, aside from melanoma and a few other cases, is often unfeasible, and thus may not capture the plasticity of interactions between the tumor and immune system under selective pressure of a given therapy. Peripheral blood analyses provide salient information about the human peripheral immunome while offering technical and practical advantages over traditional tumor biopsies, and should be utilized where possible alongside interrogation of the tumor. Some common blood-based biomarkers used to study the immune response include immune cell subsets, circulating tumor DNA, and protein analytes such as cytokines. With the recent explosion of immune checkpoint inhibitors (ICI) as a modality of treatment in multiple cancer types, soluble immune checkpoints have become a relevant area of investigation for peripheral immune-based biomarkers. However, the exact functions of soluble immune checkpoints and their roles in cancer for the most part remain unclear. This review discusses current literature on the production, function, and expression of nine soluble immune checkpoints - sPD-L1, sPD-1, sCTLA4, sCD80, sTIM3, sLAG3, sB7-H3, sBTLA, and sHVEM - in patients with solid tumors, and explores their role as biomarkers of response to ICI as well as to conventional therapies (chemotherapy, radiotherapy, targeted therapy, and surgery) in cancer patients.

Keywords: Biomarkers; Blood analyses; Conventional cancer therapies; Immune checkpoint inhibitors; Peripheral immunome; Soluble immune checkpoints.

Fig. 1

Membrane-bound (A) and soluble (B) immune checkpoints. Soluble immune checkpoints are produced through cleavage of the membrane-bound immune checkpoint proteins and/or alternative splicing of mRNA. ICOS, inducible T cell co-stimulator; B7RP1, B7-related protein 1; CTLA4, cytotoxic T-lymphocyte-associated antigen 4; PD-1, programmed cell death protein 1; PD-L1, programmed cell death-ligand 1; PD-L2, programmed cell death-ligand 2; TIM3, T cell immunoglobulin and mucin domain-containing protein 3; GAL9, galectin 9; LAG3, lymphocyte activation gene 3; MHC, major histocompatibility complex; BTLA, B and T lymphocyte attenuator; HVEM, herpesvirus entry mediator; TIGIT, T cell immunoglobulin and ITIM domain

Fig. 2

Elevated baseline levels of soluble immune checkpoints correlate with worse response to immune checkpoint therapy. Kaplan–Meier curves showing (A) progression-free survival (PFS) and (B) overall survival (OS) in NSCLC patients treated with anti-PD-1 or anti-PD-L1 monotherapy based on pre-treatment plasma sPD-L1 levels. Pre-treatment levels of sBTLA associated with OS of patients with advanced cancers treated with anti-PD-1 or the combination of anti-PD-1 plus anti-CTLA4 or other immune checkpoint inhibitors (C). Panels (A) and (B) modified from Himuro, Cancer Immunol Immunother, 2023 [78]. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC. Creative Commons CC-BY-NC license Copyright © 2023, Himuro et al., under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature. Panel (C) modified from Gorgulho, Int J Cancer, 2021 [83]. © 2021 Gorgulho et al. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC. Creative Commons CC-BY-NC license

Fig. 3

Post-treatment levels of soluble immune checkpoints after immune checkpoint therapy associate with patient response. The change in circulating levels of sPD-L1 at the first tumor evaluation (2 months after the initiation of nivolumab treatment) compared to baseline associated with progression-free survival (PFS) (A) and overall survival (OS) (B) in advanced NSCLC patients. Post treatment levels of the soluble immune checkpoints sTIM3, sBTLA4, sHVEM, sCTLA4, sPD-L1 and sPD-1 were higher after treatment with nivolumab in non-responding (NR) vs responding (R) patients with NSCLC (C). In this study, post treatment levels of sPD-L1, sTIM3, and sBTLA4 also associated with PFS (D). Panels (A and B) from Constantini, Oncoimmunology April 20, 2018 [86]. Reprinted by permission of the publisher Taylor & Francis Ltd., http://www.tandfonline.com. Panels (C and D) modified from Zizzari, J Pers Med 2020 [90]. Copyright © 2020 by Zizzari et al. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/)

Fig. 4

Elevated baseline levels of sPD-L1 correlate with worse response to conventional therapies. Advanced gastric cancer patients treated with chemotherapy were stratified by overall survival (OS) (A) and progression-free survival (PFS) (B) based on baseline levels of sPD-L1. In this study, levels of sPD-L1 prior to therapy were also significantly lower in those patients developing partial response (PR) or stable disease (SD) after chemotherapy compared to patients developing progressive disease (C). Analyses in A and B were performed using the Kaplan–Meier method and the log rank test and in C with an unpaired t-test. D Upper tract urothelial carcinoma patients treated with chemotherapy were stratified by overall survival based on baseline levels of sPD-L1 ≥ vs < 96.1 pg/mL. PD, progressive disease. Panels (A-C) modified from Shin, Sci Rep 2023 [218]. Copyright © 2023, Shin et al. Open access license Creative Commons CC BY. Panel (D) modified from Szeles, Biomedicines 2022 [89]. © 2022 by Szeles et al. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/)

Fig. 5

Elevated baseline levels of soluble immune checkpoints correlate with worse response to conventional therapies. Kaplan-Meier analysis of overall survival (OS) in patients with pancreatic ductal adenocarcinoma treated with chemotherapy stratified by baseline levels of sPD-1 and sBTLA (A) in a learning cohort (left) and validation cohort (right). Levels of sCTLA4 prior to therapy in colorectal cancer patients treated with surgery associated with both OS (B) and disease-free survival (C). Panel (A) modified from Bian, OncoImmunology, 2019 [219]. Reprinted by permission of the publisher Taylor & Francis Ltd., http://www.tandfonline.com. Panels (B and C) modified from Omura, Cancer Immunol Immunother 2020 [226]. Reproduced with permission from Springer Nature, https://www.springernature.com/gp

Fig. 6

Post treatment levels of sPD-L1 after conventional therapy associate with patient response. Kaplan–Meier analyses of (A) progression-free survival (PFS) and (B) overall survival (OS) in hepatocellular carcinoma patients with sPD-L1 levels > vs < 14.60 pg/ml after treatment with radiotherapy. The degree of change in sPD-L1 after radiotherapy compared to baseline also associated with overall response rate (C), PFS (D), and OS (E). Panels (A-E) from Zhang, Transl Oncol, 2022 [232]. Copyright © 2022. Published by Elsevier Inc