Abstract
Some reports showed encouraging efficacy of immune checkpoint inhibitors among patients who experienced immune-related adverse events (irAEs). Thus, characterization of T-cell repertoire and immune signatures in peripheral blood mononuclear cells (PBMCs) and tumors before and after immune checkpoint inhibitors treatment should contribute to better understanding of irAE-provoked anticancer immune responses. We applied expression analysis of immune-related genes and T-cell receptor sequencing in tumor and PBMCs from five patients with renal cell carcinoma before combined immunotherapy and at the onset of severe irAEs. We found that the cluster of differentiation 8 (CD8)/forkhead box P3(FOXP3), granzyme B(GZMB)/CD3, perforin 1(PRF1)/CD3 and programmed cell death 1(PD1)/CD8 expression ratios were significantly elevated in PBMCs at the onset of irAEs. In addition, we found expansion of certain T-cell clones in metastatic tissue after irAEs, which were already increased in peripheral blood at the onset of irAEs. irAE-provoked T-cells may also circulate and attack distant tumors, leading to durable response in patients with irAEs.
Highlights
Provoked T-cells may circulate and attack distant tumors, leading to durable response in patients with immune-related adverse events (irAEs)
We examined transcriptional levels of 12 genes [cluster of differentiation 3 (CD3), Cluster of differentiation 8 (CD8), Cluster of differentiation 4 (CD4), forkhead box P3 (FOXP3), granzyme B (GZMB), perforin 1 (PRF1), Cluster of differentiation 39 (CD39), Cluster of differentiation 103 (CD103), killer cell lectin-like receptor G1 (KLRG1), programmed cell death 1 (PD1), cytotoxic T-lymphocyte antigen 4 (CTLA4), and T-cell immunoglobulin and mucin domain-containing protein 3 (TIM3)] associated with cytotoxic T-cells, effector T-cells, and exhausted T-cells in peripheral blood mononuclear cells (PBMCs)
To analyze the changes of complementarity determining region 3 (CDR3) clonotypes in PBMCs, we focused on a total of 44 abundant CDR3 clonotypes (≥1% frequency among total TCR alpha (TCRA) and TCRB reads) which were expanded in the pancreatic metastasis
Summary
Provoked T-cells may circulate and attack distant tumors, leading to durable response in patients with irAEs. It was reported that the response rate and survival did not differ between patients with advanced melanoma who did and did not discontinue because of irAEs (CheckMate 069 and 067 studies) [4, 5]. These findings led to the hypothesis that patients with irAEs may have a strong autoimmune response and anticancer response as a result of reinvigoration of exhausted Tcells with ICIs. The immune mechanisms of durable clinical response after developing irAEs remain unclear. Cluster of differentiation 3 (CD3) Forkhead box P3 Cluster of differentiation 4 (CD4) Cluster of differentiation 8 (CD8) Granzyme B Perforin 1 Cytotoxic T-lymphocyte associated protein 4 (CTLA4) Programmed cell death 1 (PD1) Cluster of differentiation 39 (CD39) Cluster of differentiation 103 (CD103) Killer cell lectin-like receptor G1 T-Cell immunoglobulin and mucin domain-containing protein 3(TIM3) Glyceraldehyde 3-phosphate dehydrogenase
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