Identification of neoantigen-specific lymphocytes for its direct use in cancer immunotherapy: another emerging application of liquid biopsy in Cancer treatment.

 

A recent research letter in Nature Medicine by Alena Gros et al has opened a novel window for treatment of cancer tumors using personalized neoantigen-specific lymphocytes. In their study they have successfully identified patient-specific repertoire of tumor reactive CD8+ lymphocytes from peripheral blood.

(a), circulating FLNAR>C-, KIF16BL>P- or SONR>C-specific lymphocytes from subject NCI-3784 (b) and KIF1BPP>S-specific lymphocytes from subject NCI-3903 (c) that were cocultured with their corresponding autologous tumor cell lines (3998mel, 3784mel and 3903mel, respectively) pretreated with or without IFN-γ. (d) Reactivity of the circulating CD8+PD-1− and CD8+PD-1+ lymphocytes from subjects NCI-3998, NCI-3784, NCI-3903, NCI-3926 and NCI-3713 to their corresponding autologous tumor cell line. Each dot represents the frequency of 4-1BB upregulation for one patient sample (n = 5). Mean ± s.e.m. is shown. (e–g) IFN-γ ELISPOT assays (e) and analysis of 4-1BB upregulation by flow cytometry (representative plots shown, gated on CD3+ cells) (f,g) of pretreatment PBMC CD8+ subsets from subjects (indicated below each graph) that were screened for recognition of the shared tumor antigens indicated. Experiments were performed without duplicates. All data are representative of at least two experiments. (h) Antigens recognized by circulating and tumor-infiltrating CD8+PD-1+ lymphocytes. Each rectangle represents a target antigen screened. (i) Deep-sequencing analysis of TRB from intratumoral CD8+ PD-1+ cells and matched pretreatment PBMC CD8+, CD8+PD-1− and CD8+PD-1+ cells (n = 7) was used to determine TRB sequence overlap between the tumor-resident CD8+PD-1+ cells and the blood-derived CD8+, CD8+PD-1− and CD8+PD-1+ cells

Fig: Recognition of tumors and self-antigens by TCRs or CD8+ T cells isolated from peripheral blood, and comparison of the specificity and TCR repertoire between circulating and tumor-infiltrating CD8+ T cell subsets.

They have 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. Also they say that they have  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, they identified neoantigenspecific lymphocytes in the peripheral blood of three of four melanoma patients which is interesting result.

Furthermore they showed that neoantigen-specific T cells and gene-engineered lymphocytes expressing neoantigenspecific T cell receptors (TCRs) isolated from peripheral blood recognized autologous tumors. Notably, the tumor-antigen specificities and TCR repertoires of the circulating and tumorinfiltrating 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 neoantigenreactive lymphocytes or TCRs to treat cancer.

However low frequency of such lymphocytes in the circulation is still the big challenge for this technique in order to make it applicable in the field of cancer treatment.

 

 


References:

Gros, Alena, et al. “Prospective identification of neoantigen-specific lymphocytes in the peripheral blood of melanoma patients.” Nature medicine22.4 (2016): 433-438.

About Vikrant Palande

Hello, this is Vikrant. I am a PhD student at Bar Ilan University, Faculty of Medicine in the Galilee. My principal scientific interests are Cancer genomics and its diagnostic applications. I am involved in studying clinical relevance of cell-free circulating DNA (cfDNA) for diagnosis, staging, prognosis and therapeutic monitoring of Gliomas Tumors.