Fingolimod and tumor-infiltrating lymphocytes in checkpoint-inhibitor treated cancer patients

Omar Hasan Ali,Oltin Tiberiu Pop,Alexandre Moulin,Thomas Hundsberger,Eva Markert,Joachim Müller,Christoph Jakob Ackermann,Lukas Flatz,Stefan Diem,Sandra Stephanie Ring,Stefanie Müller,Fiamma Berner

doi:10.1007/s00262-020-02693-7

Abstract

Immune checkpoint inhibitors (ICIs) are emerging as the new standard of care for treating various metastatic cancers. It is known that effective anti-tumor immune responses are associated with a stronger presence of tumor-infiltrating lymphocytes (TILs) in solid tumor tissue. Cancer patients with relapsing–remitting multiple sclerosis (RRMS) are often under continuous treatment with fingolimod, an immune-modulating drug that inhibits lymphocyte egress from secondary lymphatic organs. Little is known about the effect of fingolimod on ICI cancer therapy, as fingolimod may limit the number of TILs. Here we present three patients with RRMS, who developed various cancers during fingolimod treatment. Histology of all tumors consistently showed low numbers of TILs. A second biopsy taken from one of the tumors, a melanoma, revealed a significant increase of TILs after stopping fingolimod and starting pembrolizumab, indicating a surge in the number and re-invigoration of T cells. Our study suggests that fingolimod limits the number of TILs in solid tumors and may, thus, inhibit anti-cancer immune responses.

Highlights

Immune checkpoint inhibitors (ICIs) have ushered in a new era in the treatment of metastatic cancer
One of the few reproducible markers is the proportion of tumor-infiltrating lymphocytes (TILs): a more pronounced pre-treatment lymphocytic infiltrate in solid tumors is associated with a better ICI therapy response [4]
Clinical data and positron emission tomography/computed tomography scans were collected from three cancer patients with relapsing–remitting Multiple sclerosis (MS) (RRMS) who were under fingolimod treatment during first cancer diagnosis

Summary

Introduction

Immune checkpoint inhibitors (ICIs) have ushered in a new era in the treatment of metastatic cancer. By targeting immune checkpoints, such as the programmed cell death protein 1 (PD1) or its ligand, ICIs lead to durable anti-cancer immune responses [1]. While they had been initially approved for therapy of metastatic melanoma and non-small cell lung cancer, they are being used for treating various malignancies and have led to significant improvement of clinical outcomes and quality of life [2, 3]. In the presence of fingolimod, S1PRs are internalized and degraded, leading to the selective retention of naïve and CM T cells in secondary lymphoid organs and reducing the migration of lymphocytes to the CNS. In addition to its selective effects on the immune system, fingolimod is thought to exert direct effects in the CNS, mainly by promoting oligodendrocyte-mediated remyelination and by reducing leakage of the blood–brain barrier [6]

Methods

Results

Conclusion