Prospective identification of neoantigen-specific lymphocytes in the peripheral blood of melanoma patients

Abstract

Detection of lymphocytes that target tumor-specific mutant neoantigens--derived from products encoded by mutated genes in the tumor--is mostly limited to tumor-resident lymphocytes, but whether these lymphocytes often occur in the circulation is unclear. We recently reported that intratumoral expression of the programmed cell death 1 (PD-1) receptor can guide the identification of the patient-specific repertoire of tumor-reactive CD8(+) lymphocytes that reside in the tumor. In view of these findings, we investigated whether PD-1 expression on peripheral blood lymphocytes could be used as a biomarker to detect T cells that target neoantigens. By using a high-throughput personalized screening approach, we identified neoantigen-specific lymphocytes in the peripheral blood of three of four melanoma patients. Despite their low frequency in the circulation, we found that CD8(+)PD-1(+), but not CD8(+)PD-1(-), cell populations had lymphocytes that targeted 3, 3 and 1 unique, patient-specific neoantigens, respectively. We show that neoantigen-specific T cells and gene-engineered lymphocytes expressing neoantigen-specific T cell receptors (TCRs) isolated from peripheral blood recognized autologous tumors. Notably, the tumor-antigen specificities and TCR repertoires of the circulating and tumor-infiltrating CD8(+)PD-1(+) cells appeared similar, implying that the circulating CD8(+)PD-1(+) lymphocytes could provide a window into the tumor-resident antitumor lymphocytes. Thus, expression of PD-1 identifies a diverse and patient-specific antitumor T cell response in peripheral blood, providing a novel noninvasive strategy to develop personalized therapies using neoantigen-reactive lymphocytes or TCRs to treat cancer.

T cell receptor richness in peripheral blood increases after cetuximab therapy and correlates with therapeutic response

“…7 Furthermore, Gros and colleagues were able to recently identify PD1 + CD8 + T cells in circulation of three melanoma patients that targeted unique patient-specific neoantigens. 31 Our findings, that tumor antigen specific T-cells (including EGFR, MAGE and HPV) in the periphery express PD-1 and CTLA-4, support these observations. Thus, circulating TA-specific T cells can be identified in peripheral blood with important consequences for the development of individualized TCR analyses and therefore personalized therapies.…”

Treatment-naïve HPV+ head and neck cancers display a T-cell-inflamed phenotype distinct from their HPV- counterparts that has implications for immunotherapy

“…34 Moreover, expression of checkpoint molecules such as PD1 on circulating CD8 + T-cells is a biomarker of tumor antigen specificity. 35 We therefore dichotomized the HPV+ HNSCC data set based on median LAG3, PD1, TIGIT, or TIM3 expression and calculated the impact of high versus low expression on overall patient survival (Figure 7, black and red curves). Higher than median expression of any of these genes predicted markedly improved survival in HPV+ HNSCC over those patients with tumors expressing these markers at levels below the median.…”

Antigen-specificity and DTIC before peptide-vaccination differently shape immune-checkpoint expression pattern, anti-tumor functionality and TCR repertoire in melanoma patients

“…Consistently, Simon et al have recently showed that PD-1 expression identifies Ag-specific T-cell clones with high avidity, 28 and Gros et al described PD-1 + neoantigen-specific anti-tumor CD8 + T cells, either circulating or intratumoral. 56 …”