C reactive protein impairs adaptive immunity in immune cells of patients with melanoma.

BACKGROUND

High C reactive protein (CRP) levels have been reported to be associated with a poor clinical outcome in a number of malignancies and with programmed cell death protein 1 immune checkpoint blockade in patients with advanced cancer. Little is known about the direct effects of CRP on adaptive immunity in cancer. Therefore, we investigated how CRP impacted the function of T cells and dendritic cells (DCs) from patients with melanoma.

METHODS

The effects of CRP on proliferation, function, gene expression and phenotype of patient T cells and DCs, and expansion of MART-1 antigen-specific T cells were analyzed by multicolor flow cytometry and RNA-seq. Additionally, serum CRP levels at baseline from patients with metastatic melanoma treated on the Checkmate-064 clinical trial were assessed by a Luminex assay.

RESULTS

In vitro, CRP inhibited proliferation, activation-associated phenotypes and the effector function of activated CD4+ and CD8+ T cells from patients with melanoma. CRP-treated T cells expressed high levels of interleukin-1β, which is known to enhance CRP production from the liver. CRP also suppressed formation of the immune synapse and inhibited early events in T-cell receptor engagement. In addition, CRP downregulated the expression of costimulatory molecules on mature DCs and suppressed expansion of MART-1-specific CD8+ T cells in a dose-dependent manner by impacting on both T cells and antigen-presenting cells. High-serum CRP levels at baseline were significantly associated with a shorter survival in both nivolumab-treated and ipilimumab-treated patients.

CONCLUSIONS

These findings suggest that high levels of CRP induce an immunosuppressive

TRIAL REGISTRATION NUMBER

NCT01783938 and NCT02983006.

Informations de copyright

© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

Déclaration de conflit d'intérêts

Competing interests: JW: honoraria and travel from BMS, Merck, GSK, Genentech, AstraZeneca, Pfizer, CytoMx, EMD Serono, Incyte. Stock in Biond, Altor, Protean, CytoMx, Celldex, Sellas. Research funding from NextCure. All other clinical research funding to my institution, not me. Named on a patent for a PD-1 biomarker by Biodesix not used in this work. Named on a CTLA-4 biomarker patent by Moffitt Cancer Center not used in this work. Named on a patent for the use of 41-BB antibody for tumor infiltrating lymphocyte growth by Moffitt Cancer Center not used in this work.