PD-1+ Polyfunctional T Cells Dominate the Periphery after Tumor-Infiltrating Lymphocyte Therapy for Cancer

Abstract

Infusion of highly heterogeneous populations of autologous tumor-infiltrating lymphocytes (TIL) can result in tumor regression of exceptional duration. Initial tumor regression has been associated with persistence of tumor-specific TILs 1 month after infusion, but mechanisms leading to long-lived memory responses are currently unknown. Here, we studied the dynamics of bulk tumor-reactive CD8 T-cell populations in patients with metastatic melanoma following treatment with TILs. We analyzed the function and phenotype of tumor-reactive CD8 T cells contained in serial blood samples of 16 patients treated with TILs. Polyfunctional tumor-reactive CD8 T cells accumulated over time in the peripheral lymphocyte pool. Combinatorial analysis of multiple surface markers (CD57, CD27, CD45RO, PD-1, and LAG-3) showed a unique differentiation pattern of polyfunctional tumor-reactive CD8 T cells, with highly specific PD-1 upregulation early after infusion. The differentiation and functional status appeared largely stable for up to 1 year after infusion. Despite some degree of clonal diversification occurring within the bulk tumor-reactive CD8 T cells, further analyses showed that CD8 T cells specific for defined tumor antigens had similar differentiation status. We demonstrated that tumor-reactive CD8 T-cell subsets that persist after TIL therapy are mostly polyfunctional, display a stable partially differentiated phenotype, and express high levels of PD-1. These partially differentiated PD-1 polyfunctional TILs have a high capacity for persistence and may be susceptible to PD-L1/PD-L2-mediated inhibition. .

Phenotype, Polyfunctionality, and Antiviral Activity of in vitro Stimulated CD8+ T-Cells From HIV+ Subjects Who Initiated cART at Different Time-Points After Acute Infection

“…This is in line with data provided by Hokey et al, who found high PD-1 expression on cells with activated memory and effector phenotypes despite decreased telomere lengths, suggesting PD-1 could play a costimulatory role in CD8 + T-cell populations ( 95 ). Moreover, a recent report showed that tumor-reactive CD8 + T-cells that persist after adoptive cell-transfer therapy, and associate with tumor regression, are mostly polyfunctional and simultaneously express high levels of PD-1 ( 96 ). This data highlights the fact that the PD-1 role in the context of viral reactivation needs further research.…”

T-cell Responses in the Microenvironment of Primary Renal Cell Carcinoma—Implications for Adoptive Cell Therapy

“…This feature is known to correlate with antigen sensitivity and TCR affinity for cognate antigen (31,32), antigen concentration (33), and, partially, differentiation status (34). We recently showed that polyfunctional T cells dominate the periphery after successful TIL therapy for cancer (35). Thus, we characterized the functional patterns of tumor-reactive CD8 þ T cells.…”

Adoptive transfer of tumor-infiltrating lymphocytes in melanoma: a viable treatment option

“…Currently, several trials have been initiated combining TIL with PD-1 blocking agents (NCT03374839, NCT03475134, NCT03158935, NCT02652455, NCT02621021, NCT01993719), see also Table 1 . Synergism from this combination may be expected as the ex vivo grown and expanded tumor-reactive TIL are often PD-1 positive [ 63 ] and prevention of the interaction between PD-1 on T cells and PDL-1 on tumor cells by anti-PD-1 therapy around the time of TIL infusion, may render these TIL more tumoricidal.…”