Selection of CD8+PD-1+ Lymphocytes in Fresh Human Melanomas Enriches for Tumor-reactive T Cells

Abstract

CD8 + Tumor infiltrating lymphocyte (TIL) in human melanomas express high levels of PD-1 and are functionally impaired. However, adoptive cell therapy using in vitro-expanded TIL can be a highly effective therapy for patients with advanced melanoma. This discrepancy led us to further analyze the CD8 + PD-1 + TILs. We found that the percentage of PD-1 expressing CD8 + T-cells was higher in the tumor digests that generate tumor-reactive TILs after in vitro culture in IL-2 (P=0.0007). Also sorted and expanded CD8 + PD-1 + T-cells in tumor digests showed much higher tumor specific IFN-γ production compared with CD8 + PD-1 -T-cells. These results suggested that tumor-specific CD8 + T-cells in melanoma tumor digests are largely PD-1 + , and this population can recover function after culturing in IL-2. PD-1 has been reported as an inhibitory receptor on T-cells. We found that the in vitro functional suppression of cultured-TILs from native levels of PD-L1 expression on melanomas was minimal, and moreover expression level of PD-1 on CD8 + tumor-specific TILs decreased during the culture. As a consequence, the PD-1 receptor can be a useful biomarker for enriching tumor specific T-cells from fresh melanomas.

PD-1 and CD103 Are Widely Coexpressed on Prognostically Favorable Intraepithelial CD8 T Cells in Human Ovarian Cancer

“…A similar scenario has recently been described in melanoma, where PD-1 was shown to specifically demarcate tumor-reactive CD8 T cells (51). Importantly, in this study, PD-1 expression on melanoma-derived TIL was shown to be rapidly downregulated after in vitro expansion, and these "reinvigorated" TIL mediated profound clinical effects after reinfusion into melanoma patients (52). If this latter finding is also applicable to ovarian cancer, then it bodes well for the possibility of using in vitro expanded PD-1 þ CD103 þ TIL for the treatment of this lethal disease.…”

Expression profiling of TCR-engineered T cells demonstrates overexpression of multiple inhibitory receptors in persisting lymphocytes

“…Functional experiments conducted ex vivo revealed that CD160 [38][39][40] we suggest that treatments involving disruption of PD-1/PD-L1 interaction by means of blocking antibodies might impact positively on the clinical outcome of ACT using geneengineered T cells. Moreover, it has been reported that PD-L1 is induced by IFNg in antigen-presenting cells 41 and melanoma cells, 42 and that PD-L1 expression in melanoma cells is higher in areas of the tumor presenting a higher T-cell infiltration, 43 suggesting that PD-L1 expression in the tumor microenvironment might be increased after ACT.…”

CD4+ follicular helper T cell infiltration predicts breast cancer survival

“…The notion that PD-1 expression on Tfh cells elicits context-dependent responses in protected lymphoid structures is supported by a recent murine study showing that PD-1 + Tfh cells survive and function in gut-associated lymphoid follicles after anti-Thy-1 antibody treatment (54). PD-1 expression is often considered a sign of T cell exhaustion; however, our expanding knowledge indicates that it can also act as a signal for other functions, highlighted by the demonstration that CD8 + PD-1 + TIL produce higher levels of IFN-γ than PD-1 -cells (55). Overall, current data suggests that, in contrast to effector T cell TIL, PD-1 + Tfh cells located in BC-associated TLS likely do not contact PD-L1 + tumor cells and are not directly affected by PD-1-mediated tumor suppression but are instead regulated by PD-1 to elicit other functions.…”