PD-1 Blockade Promotes Epitope Spreading in Anticancer CD8+ T Cell Responses by Preventing Fratricidal Death of Subdominant Clones To Relieve Immunodomination

Abstract

The interactions between programmed death-1 (PD-1) and its ligands hamper tumor-specific CD8+ T cell (TCD8) responses, and PD-1-based ‘checkpoint inhibitors’ have shown promise in certain cancers, thus revitalizing interest in immunotherapy. PD-1-targeted therapies reverse TCD8 exhaustion/anergy. However, whether they alter the epitope breadth of TCD8 responses remains unclear. This is an important question because subdominant TCD8 are more likely than immunodominant clones to escape tolerance mechanisms and may contribute to protective anticancer immunity. We have addressed this question in an in vivo model of TCD8 responses to well-defined epitopes of a clinically relevant oncoprotein, large T antigen. We found that unlike other co-inhibitory molecules (CTLA-4, LAG-3, TIM-3), PD-1 was highly expressed by subdominant TCD8, which correlated with their propensity to favorably respond to PD-1/PD-L1-blocking antibodies. PD-1 blockade increased the size of subdominant TCD8 clones at the peak of their primary response, and also sustained their presence giving rise to an enlarged memory pool. The expanded population was fully functional as judged by IFN-γ production and MHC I-restricted cytotoxicity. The selective increase in subdominant TCD8 clonal size was due to their enhanced survival, not proliferation. Further mechanistic studies utilizing peptide-pulsed dendritic cells, recombinant vaccinia viruses encoding full-length T antigen or epitope mingenes, and tumor cells expressing T antigen variants revealed that anti-PD-1 invigorates subdominant TCD8 responses by relieving their lysis-dependent suppression by immunodominant TCD8. Our work constitutes the first report that interfering with PD-1 signaling potentiates epitope spreading in tumor-specific responses, a finding with clear implications for cancer immunotherapy and vaccination.

B7-H1 maintains the polyclonal T cell response by protecting dendritic cells from cytotoxic T lymphocyte destruction

“…However, we had yet to determine if the focused TCR repertoire was associated with a loss in TCR recognizing subdominant Ags and subsequent recurrence of tumors, which we predict from our study. A recent mouse model study using viral SV40 large T Ag, however, showed that anti-PD therapy could promote epitope spreading by preventing fratricidal death of subdominant T cells (31). This finding is different from our results because we did not observe significant death of T cells recognizing dominant and subdominant Ags in our models.…”

MEK inhibition enhances oncolytic virus immunotherapy through increased tumor cell killing and T cell activation

“…We found evidence for both viral (HSV-1 gB-specific) and melanoma (gp100-and TRP2-specific) CD8 + T cell responses, consistent with initial viral responses followed by cross presentation of tumor-associated antigens (34). Antigen spreading has previously been reported as a predictive biomarker of therapeutic responses for other forms of immunotherapy, including tumor vaccines and immune checkpoint inhibitors (35,36). We further observed that combination therapy promoted an IFN--regulated gene signature profile that has been associated with therapeutic responses to PD-1 blockade in patients with melanoma (18).…”

Influence of Inflammation in the Process of T Lymphocyte Differentiation: Proliferative, Metabolic, and Oxidative Changes

“…As a result, depending on their level of expression on the cell surface, CTLA-4 may interfere with CD80/CD86 binding. Several more inhibitors, such as lymphocyte activation gene 3, and V-domain Ig suppressor of T lymphocyte activation have been described, blocking these inhibitors by specific antibodies are being studied to increase the immune response in numerous cancers ( 42 , 43 ).…”