The Road Death Travelled: How FcgRIIB regulates CD8+ T cell immunity Restricted; Files Only
Bennion, Kelsey (Spring 2024)
Abstract
Cancer immunotherapies have revolutionized patient outcomes in the clinic, but the variability in patient response underscores the need to identify immunologic factors leading to differential therapeutic success. An ever-growing body of evidence supports the importance of CD8+ T cells in promoting patient immunotherapeutic response. Thus, there is great interest in the discovery and manipulation of additional regulatory pathways of the antigen-specific CD8+ T cell response. We recently showed that FcγRIIB, the only inhibitory IgG-Fc receptor, is expressed on a subset of effector memory-like CD8+ T cells in mice and humans. Here, we show that FcγRIIB+ tumor-infiltrating CD8+ possess higher proliferative ability and secrete more proinflammatory cytokines than their FcγRIIB- counterparts, making them imperative to the antitumor response. As immune checkpoint blockade uses Fc-containing monoclonal antibodies to augment anti-tumor immunity, the discovery of CD8+ T cell-expressed FcγRIIB raised the possibility that CD8+ T cell responses may be directly modulated by checkpoint inhibitor binding to T cell-expressed FcγRIIB. Here, we show that Fc-containing immune checkpoint antibodies can elicit a counterproductive signal to otherwise potent memory CD8+ T cells through FcγRIIB. We also show the potential clinical utility of blocking FcγRIIB in several murine models of cancer. These results illuminate an FcγRIIB-mediated, cell-autonomous mechanism of CD8+ T cell suppression that limits the efficacy of immune checkpoint antibodies.
In addition to therapeutic antibody, we previously discovered that the immunosuppressive cytokine fibrinogen-like protein 2 (Fgl2) may serve as an endogenous ligand of FcγRIIB on CD8+ T cells in vitro. Within these pages, we show that Fgl2 serves as a ligand of FcγRIIB on CD8+ T cells in vivo. We found that macrophage-secreted Fgl2 bound FcγRIIB on CD8+ T cells to negatively regulate CD8+ T cells independent of an antigen-presenting cell intermediary. Unexpectedly, we also discovered that exhausted CD8+ T cells could produce Fgl2 to then induce apoptosis of FcγRIIB+ CD8+ in an auto-regulatory feedback loop. From these data, we concluded that CD8+ T-cell secreted Fgl2 dampened the T cell response to tumor and chronic virus. In contrast to the current widely-held view, these data show that exhausted T cells are not functionally inert but actively participate in the resolution of an immune response by inducing deletion of antigen-specific CD8+ T cells along the Fgl2/FcγRIIB axis. In this way, Fgl2-expressing exhausted T cells contribute to the prevention of immune pathology and the return to immune homoeostasis.
Because CD8+ T cells are a driving factor in the rejection of transplanted organs, we asked if graft-specific CD8+ T cells could also secrete Fgl2 in a murine model of skin allograft. Indeed, we found that CD8+ secreted Fgl2 could prolong allograft acceptance and may be a way to amplify the immunoregulatory functions inherent in alloreactive CD8+ T cells to promote allograft tolerance.
In sum, these data support the role of Fgl2 in regulating the T-cell response to tumor, virus, and allograft. These studies also highlight the potential clinical importance of the Fgl2-FcγRIIB pathway on CD8+ T cells and demonstrate a regulatory signaling axis whereby effector-like memory CD8+ T cells produce their own off-switch. The data presented here delineate how CD8+ T cell-expressed FcγRIIB regulates the antigen-specific CD8+ T cell response in a cell-intrinsic manner through therapeutic IgG as well as endogenously present Fgl2.
Table of Contents
Abstract....................................................................................................................................... ii
Acknowledgements...................................................................................................................................... iv
Table of Contents...................................................................................................................................... vi
List of Figures...................................................................................................................................... ix
List of Tables.................................................................................................................................... .xii
Chapter 1: Introduction........................................................................................................................................ 1
1.1 Introduction............................................................................................................................ 1
1.2 The role of T cells in health and malignancy............................................................................................................................ 1
1.3 Regulatory mechanisms governing T cell activation........................................................................................................................................ 3
1.4 Cancer immunotherapeutic approaches targeting T cell regulatory mechanisms........................................................................................................................................ 9
1.5 T cell determinants of patient response to immunotherapies...................................................................................................................................... 12
1.6 Premise and goals of this work...................................................................................................................................... 14
Chapter 2: FcγRIIB expressed on CD8+ T cells limits responsiveness to PD-1 checkpoint inhibition in cancer...................................................................................................................................... 16
2.1 Abstract.......................................................................................................................... 17
2.2 Introduction.......................................................................................................................... 18
2.3 Results.......................................................................................................................... 20
2.4 Discussion.......................................................................................................................... 33
2.5 Materials and Methods.......................................................................................................................... 36
2.6 Acknowledgments.......................................................................................................................... 45
Chapter 3: Macrophage-derived Fgl2 dampens antitumor immunity through regulation of FcγRIIB+ CD8+ T cells...................................................................................................................................... 80
3.1 Abstract.......................................................................................................................... 81
3.2 Introduction.......................................................................................................................... 82
3.3 Results.......................................................................................................................... 84
3.4 Discussion.......................................................................................................................... 89
3.5 Materials and Methods.......................................................................................................................... 92
3.6 Acknowledgments.......................................................................................................................... 97
Chapter 4: CD8+ T cell-derived Fgl2 regulates immunity in a cell-autonomous manner.................................................................................................................................... 116
4.1 Abstract........................................................................................................................ 117
4.2 Introduction........................................................................................................................ 118
4.3 Results........................................................................................................................ 119
4.4 Discussion........................................................................................................................ 128
4.5 Materials and Methods........................................................................................................................ 131
4.6 Acknowledgments........................................................................................................................ 138
Chapter 5: Fgl2 secretion by CD8+ T cells prolongs allograft acceptance in a cell-intrinsic manner.................................................................................................................................... 163
5.1 Abstract........................................................................................................................ 164
5.2 Introduction........................................................................................................................ 165
5.3 Results........................................................................................................................ 166
5.4 Discussion........................................................................................................................ 170
5.5 Methods........................................................................................................................ 172
5.6 Acknowledgments........................................................................................................................ 176
Chapter 6: Conclusions and Closing Remarks.................................................................................................................................... 189
6.1 Mechanisms of resistance to immune checkpoint blockade........................................................................................................................ 189
6.2 T-cell intrinsic and T-cell extrinsic mechanisms of cell death........................................................................................................................ 192
6.3 Bridging the gap in cancer and transplant to study T cell immunity........................................................................................................................ 198
Chapter 7: References.................................................................................................................................... 199
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File download under embargo until 22 May 2026 | 2024-04-24 18:22:26 -0400 | File download under embargo until 22 May 2026 |
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