Peripheral Blood Immune Cell-based Biomarkers in Anti-PD-1/PD-L1 Therapy

Kyung Hwan Kim; Chang Gon Kim; Eui-Cheol Shin

doi:10.4110/in.2020.20.e8

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Kim, Kim, and Shin: Peripheral Blood Immune Cell-based Biomarkers in Anti-PD-1/PD-L1 Therapy

Review Article

Immune Netw 2020;20(1):e8.

Published online: 4 February 2020

DOI: https://doi.org/10.4110/in.2020.20.e8

Peripheral Blood Immune Cell-based Biomarkers in Anti-PD-1/PD-L1 Therapy

Kyung Hwan Kim^†, Chang Gon Kim^†, Eui-Cheol Shin^*

Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon 34141, Korea

^*Correspondence to Eui-Cheol Shin Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology (KAIST), 291 Daehak-ro, Yuseong-gu, Daejeon 34141, Korea. E-mail: ecshin@kaist.ac.kr

^† These authors contributed equally to this work.

Conflict of Interest The authors declare no potential conflicts of interest.

Received 6 January 2020 Revised 29 January 2020 Accepted 30 January 2020

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Immune checkpoint blockade targeting PD-1 and PD-L1 has resulted in unprecedented clinical benefit for cancer patients. Anti-PD-1/PD-L1 therapy has become the standard treatment for diverse cancer types as monotherapy or in combination with other anti-cancer therapies, and its indications are expanding. However, many patients do not benefit from anti-PD-1/PD-L1 therapy due to primary and/or acquired resistance, which is a major obstacle to broadening the clinical applicability of anti-PD-1/PD-L1 therapy. In addition, hyperprogressive disease, an acceleration of tumor growth following anti-PD-1/PD-L1 therapy, has been proposed as a new response pattern associated with deleterious prognosis. Anti-PD-1/PD-L1 therapy can also cause a unique pattern of adverse events termed immune-related adverse events, sometimes leading to treatment discontinuation and fatal outcomes. Investigations have been carried out to predict and monitor treatment outcomes using peripheral blood as an alternative to tissue biopsy. This review summarizes recent studies utilizing peripheral blood immune cells to predict various outcomes in cancer patients treated with anti-PD-1/PD-L1 therapy.

Keywords: Blood, Biomarkers, PD-1 receptor, Programmed cell death 1 ligand 1, Prognosis, Adverse drug event

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Table 1.

Summary of relevant biomarker studies predicting treatment response and prognosis

Biomarker	Cancer type	No. of patients	Main results	Reference
(%Ki-67⁺ cells/PD-1⁺ CD8⁺ T cells 3-wk post-treatment)/baseline	Melanoma	Discovery cohort: 23	Higher Ki67/TB significantly associated with superior ORR (p=0.03) and PFS (p=0.004).	Huang et al. (34)
tumor burden (Ki67/TB)		Validation cohort: 18	Higher Ki67/TB associated with superior ORR (p=0.14) and PFS (p=0.06).
(%Ki-67⁺ cells/PD-1⁺ CD8⁺ T cells 1-wk post-treatment)/(%Ki-67⁺ cells/PD-1⁺ CD8⁺ T cells at	TET	Discovery cohort: 31	Higher Ki-67 _D7/D0 significantly associated with durable clinical benefit (PR, or SD for 6 months or longer; p<0.001) and PFS (p=0.027)	Kim et al. (32)
baseline) (Ki-67 _D7/D0)	NSCLC	Discovery cohort: 33	Higher Ki-67 _D7/D0 significantly associated with durable clinical benefit (PR, or SD for 6 months or longer; p<0.01), PFS (p=0.004), and OS (p=0.001)
		Validation cohort: 46	Higher Ki-67 _D7/D0 significantly associated with durable clinical benefit (PR, or SD for 6 months or longer; p<0.01), PFS (p=0.002), and OS (p=0.037)
%FoxP3⁻ PD-1 ^hi CD4⁺ T cells/ CD4⁺ T cells (4PD1 ^hi) 3-wk post-treatment Fold change of 4PD1^hi	Melanoma	52	Higher frequency of 4PD1 ^hi 3-wks post treatment (p=0.0005) and fold change of 4PD1 ^hi (p=0.046) associated with poorer OS.	Zappasodi et al. (36)
TCR diversity of PD-1⁺ CD8⁺ T cells at baseline and post-treatment	NSCLC	Discovery cohort: 25 Validation cohort: 15	Higher baseline diversity in PD-1⁺ CD8⁺ T cells (p=0.021) and increased clonality after treatment (p=0.002) associated with superior PFS.	Han et al. (39)
%CD27⁻ CD28⁻ cells/CD4⁺ T cells at baseline	NSCLC	51	Higher frequency of CD27⁻ CD28⁻ CD4⁺ T cells associated superior PFS (p=0.001).	Zuazo et al. (42)
Ratio of the frequency of Treg cells and PMN-MDSCs at baseline	NSCLC	Discovery cohort: 34 Validation cohort: 29	Higher ratio of the frequency of Treg cells and PMN-MDSCs associated with superior PFS (p=0.0079). Higher ratio of the frequency of Treg cells and PMN-MDSCs associated with superior PFS (p=0.0017).	Kim et al. (44)
%Effector/memory (CCR7⁻ CD45RA⁻) cells/CD8⁺ T cells at baseline	NSCLC	263 (flow cytometry analysis in 144)	Lower frequency of effector/memory CD8⁺ T cells with development of hyperprogressive disease (p<0.001) and poor PFS (p<0.001) and OS (p<0.001).	Kim et al. (53)
%TIGIT⁺ cells/PD-1⁺ CD8⁺ T cells at baseline			Higher frequency of TIGIT⁺ cells among PD-1⁺ CD8⁺ T cells in peripheral blood at baseline significantly associated with development of hyperprogressive disease (p<0.001) and poor PFS (p<0.001) and OS (p=0.01).

NSCLC, non-small-cell lung cancer; ORR, objective response rate; OS, overall survival; PFS, progression-free survival; PR, partial response; SD, stable disease; TET, thymic epithelial tumor; CCR7, C-C chemokine receptor type 7.

Table 2.

Summary of relevant biomarker studies predicting irAEs

Biomarker	Cancer type	No. of patients	Main results	Reference
Fold change of effector Treg cells 1-wk post-treatment Th17 to Th1 ratio at baseline %Ki-67⁺/PD-1⁺CD8⁺ T cells 1-wk post-treatment %TNF-α⁺/CD4⁺ or CD8⁺ T cells 1-wk post-treatment	TET NSCLC	31 60	Patients with irAEs can be distinguished into 4 distinct subtypes according to the T-cell parameters and each T-cell parameter predicts the corresponding subtype of irAEs	Kim et al. (63)
Memory cytotoxic (CD45RO⁺ GzmB⁺ Ki-67⁺) CD4⁺ T cells	Melanoma	3	Activated memory CD4⁺ T cells were highly enriched in inflammed, affected region of cases with encephalitis.	Johnson et al. (68)
Early B cell changes (decline in B cells, increase in CD21 ^lo B cells)	Melanoma	23	Decline in B cells but an increase in CD21 ^lo B cells more prominent in patients with severe irAEs that received combined anti-PD-1 and anti-CTLA-4	Das et al. (72)
Cytokine expression-based score	Melanoma	Discovery cohort: 98	Eleven cytokines were integrated into a single score (CYTOX) and it significantly predicted development of severe irAEs in patients treated with combined anti-PD-1 and anti-CTLA-4.	Lim et al. (77)
		Validation cohort: 49	CYTOX score significantly predicted development of severe irAEs.
Auto-Abs (rheumatoid factor, antinuclear Ab, antithyroglobulin, and antithyroid peroxidase)	NSCLC	137	Preexisting rheumatoid factor or auto-Abs significantly correlates with development of any grade irAEs	Toi et al. (75)
Anti-thyroid Abs (anti-microsomal and anti-thyroglobulin)	NSCLC	51	Presence of anti-thyroid Abs either at baseline or during anti-PD-1 treatment was significantly associated with thyroid dysfunction	Osorio et al. (76)

NSCLC, non-small-cell lung cancer; TET, thymic epithelial tumor.

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