Evidence for Non-Cancer-Specific T Cell Exhaustion in the Tcl1 Mouse Model for Chronic Lymphocytic Leukemia.

Thomas Parigger,Kemal Catakovic,Markus Steiner,Jan Philip Höpner,Alexandra Hödlmoser,Roland Geisberger,Christian Scherhäufl,Franz Josef Gassner,Aryunni Abu Bakar,Nadja Zaborsky,Richard Greil

doi:10.3390/ijms22136648

Abstract

The reinvigoration of anti-cancer immunity by immune checkpoint therapies has greatly improved cancer treatment. In chronic lymphocytic leukemia (CLL), patients as well as in the Tcl1 mouse model for CLL, PD1-expressing, exhausted T cells significantly expand alongside CLL development; nevertheless, PD1 inhibition has no clinical benefit. Hence, exhausted T cells are either not activatable by simple PD1 blocking in CLL and/or only an insufficient number of exhausted T cells are CLL-specific. In this study, we examined the latter hypothesis by exploiting the Tcl1 transgenic CLL mouse model in combination with TCR transgene expression specific for a non-cancer antigen. Following CLL tumor development, increased PD1 levels were detected on non-CLL specific T cells that seem dependent on the presence of (tumor-) antigen-specific T cells. Transcriptome analysis confirmed a similar exhaustion phenotype of non-CLL specific and endogenous PD1pos T cells. Our results indicate that in the CLL mouse model, a substantial fraction of non-CLL specific T cells becomes exhausted during disease progression in a bystander effect. These findings have important implications for the general efficacy assessment of immune checkpoint therapies in CLL.

Highlights

The acquisition of cancer-specific mutations and splicing patterns normally leads to the expression of cancer-specific antigens and to a cancer-specific immunopeptidome presented on MHC molecules [1,2,3]
We compared the induction of PD1 upregulation on T cells as a surrogate marker for T cell exhaustion upon transplantation of chronic lymphocytic leukemia (CLL) cells from the Tcl1 CLL mouse model into the congenic WT and OT1/OT2 mice as recipients (Figure 1A)
As ovalbumin is not expressed in our mouse models, any T cells expressing the transgenic TCR, which are identifiable by staining with a TCR-Vb5-specific antibody, were defined as non-CLLspecific

Summary

Introduction

The acquisition of cancer-specific mutations and splicing patterns normally leads to the expression of cancer-specific antigens and to a cancer-specific immunopeptidome presented on MHC molecules [1,2,3] This should result in the recognition of cancer cells by the host’s immune system, a robust anti-cancer immune response is frequently rendered ineffective due to many immunosuppressive mechanisms from the cancer cells and the cancer microenvironment [4]. T cell exhaustion was originally discovered in mouse models investigating chronic, persisting virus infections Within such chronic settings, virus-specific T cells, characterized by the expression of the inhibitory receptor PD1, are silenced to avoid overwhelming tissue destruction and immune pathologies [6]. The aim of this study is to elucidate whether T cell exhaustion is confined to tumor-specific T cells or whether this dysfunctional phenotype affects T cells independently of recognizing tumor antigens

Objectives

Results

Conclusion