T-cell CX3CR1 expression as a dynamic blood-based biomarker of response to immune checkpoint inhibitors

Takayoshi Yamauchi,Brahm H Segal,Fumito Ito,Kunle Odunsi,Kristopher Attwood,Takaaki Oba,Sebastiano Battaglia,Saby George,Hongbin Chen,Carl Morrison,Gurkamal Chatta,Toshifumi Hoki,Vaibhav Jain,Grace K Dy,Igor Puzanov,Marc S Ernstoff

doi:10.1038/s41467-021-21619-0

Abstract

Immune checkpoint inhibitors (ICI) have revolutionized treatment for various cancers; however, durable response is limited to only a subset of patients. Discovery of blood-based biomarkers that reflect dynamic change of the tumor microenvironment, and predict response to ICI, will markedly improve current treatment regimens. Here, we investigate CX3C chemokine receptor 1 (CX3CR1), a marker of T-cell differentiation, as a predictive correlate of response to ICI therapy. Successful treatment of tumor-bearing mice with ICI increases the frequency and T-cell receptor clonality of the peripheral CX3CR1+CD8+ T-cell subset that includes an enriched repertoire of tumor-specific and tumor-infiltrating CD8+ T cells. Furthermore, an increase in the frequency of the CX3CR1+ subset in circulating CD8+ T cells early after initiation of anti-PD-1 therapy correlates with response and survival in patients with non-small cell lung cancer. Collectively, these data support T-cell CX3CR1 expression as a blood-based dynamic early on-treatment predictor of response to ICI therapy.

Highlights

Immune checkpoint inhibitors (ICI) have revolutionized treatment for various cancers; durable response is limited to only a subset of patients
To further elucidate this mechanism, we evaluated CX3C chemokine receptor 1 (CX3CR1) expression, a marker of T-cell differentiation in combination with CD27 29–31, on peripheral blood (PB) CD8+ T cells before and during treatment with anti-PD1 ligand-1 (PD-L1) and anti-cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) Ab or isotype Ab (NT: no-treatment) in two mouse tumor models, MC38 and CT26 colon adenocarcinoma (Fig. 1a and Supplementary Fig. 1)
We used a tetramer (Tet) to detect CD8+ T cells specific for mutated Adpgk protein (AdpgkMut) in MC38 and shared tumor-associated antigen (TAA), gp[70] in CT26 tumors[36,37], and found substantially increased frequency of CX3CR1+ Tet+ CD8+ T cells in both tumor models (Fig. 1d), suggesting that T-cell differentiation after ICI therapy occurs in tumor-specific CD8+ T cells

Summary

Introduction

Immune checkpoint inhibitors (ICI) have revolutionized treatment for various cancers; durable response is limited to only a subset of patients. We investigate CX3C chemokine receptor 1 (CX3CR1), a marker of T-cell differentiation, as a predictive correlate of response to ICI therapy. An increase in the frequency of the CX3CR1+ subset in circulating CD8+ T cells early after initiation of anti-PD-1 therapy correlates with response and survival in patients with non-small cell lung cancer. These data support T-cell CX3CR1 expression as a blood-based dynamic early on-treatment predictor of response to ICI therapy. Evidence from preclinical and clinical studies prompted us to evaluate the role of CX3CR1 as a blood-based T-cell biomarker of response to ICI therapy

Methods

Results

Conclusion