Clonality of CD4+ Blood T Cells Predicts Longer Survival With CTLA4 or PD-1 Checkpoint Inhibition in Advanced Melanoma

Abstract

Recognition of cancer antigens drives the clonal expansion of cancer-reactive T cells, which is thought to contribute to restricted T-cell receptor (TCR) repertoires in tumor-infiltrating lymphocytes (TILs). To understand how tumors escape anti-tumor immunity, we investigated tumor-associated T-cell repertoires of patients with advanced melanoma and after blockade of the cytotoxic T-lymphocyte-associated protein 4 (CTLA4) or programmed cell death 1 (PD-1). TCR Vβ-gene spectratyping allowed us to quantify restrictions of T-cell repertoires and, further, diversities of T-cell clones. In this study, we show that the blood TCR repertoires were variably restricted in CD4 + and extensively restricted in CD8 + T cells of patients with advanced melanoma, and contained clones in both T-cell fractions prior to the start of immunotherapy. A greater diversification especially of CD4 + blood T-cell clones before immunotherapy showed statistically significant correlations with long-term survival upon CTLA4 or PD-1 inhibition. Analysis of TILs and corresponding blood available in one patient indicated that blood clonality may at least partially be related to the clonal expansion in the tumor microenvironment. In patients who developed severe immune-related adverse events (IrAEs), CD4 + and CD8 + TCR spectratypes became more restricted during anti-CTLA4 treatment, suggesting that newly expanded oligoclonal T-cell responses may contribute to IrAEs. This study reveals diverse T-cell clones in the blood of melanoma patients prior to immunotherapy, which may reflect the extent to which T cells are able to react against melanoma and potentially control melanoma progression. Therefore, the T-cell clonality in the circulation may have predictive value for antitumor responses from checkpoint inhibition.

Mapping the Immune Landscape of Clear Cell Renal Cell Carcinoma by Single-Cell RNA-seq

“…Moreover, circulating CD4 + TCR repertoire showed less diversity compared with circulating CD8 + . This is of particular interest given that greater diversity of CD4 + blood T-cell clones before immunotherapy has been significantly correlated with long-term survival upon CTLA4 or PD-1 inhibition in melanoma (49). We revealed that a substantial portion of intratumoral Tregs showed higher expression of FOXP3 and other transcripts for effector T cell suppression genes involved in essential Treg function, as recently reported in a non-tumor context (50).…”

Pegylated recombinant human granulocyte colony‐stimulating factor regulates the immune status of patients with small cell lung cancer

“…Previous studies showed that T cell clones circulating in the blood may correspond to tumor‐infiltrating lymphocytes in melanoma, some of which may have expanded in response to tumor antigens . The TCR clonality of both CD4 + and CD8 + T cells is more restricted than in healthy people, and broader T cell responses with greater diversity of CD4 + blood T cell clones may predict the longer survival of patients with melanoma treated with anti‐CTLA4 or PD‐1 antibodies . Many studies have shown that peripheral blood TCR diversity can be used to predict the efficacy of immunotherapy .…”

“…19,[30][31][32] The TCR clonality of both CD4 + and CD8 + T cells is more restricted than in healthy people, and broader T cell responses with greater diversity of CD4 + blood T cell clones may predict the longer survival of patients with melanoma treated with anti-CTLA4 or PD-1 antibodies. 19 Many studies have shown that peripheral blood TCR diversity can be used to predict the efficacy of immunotherapy. 17,21,33,34 Therefore, PEG-rhG-CSF may improve the efficacy of immunotherapy by increasing peripheral blood TCR diversity; however, further clinical studies are needed to confirm this.…”

“…TCR diversity is predominantly derived from the highly variable complementarity‐determining region 3 (CDR3) and is generated by random rearrangement and junction region mutation of the V‐D‐J regions, which are three fragments located in TCR‐coding genes. Many studies have shown that lymphocytes recognize the patient's unique mutations in the peripheral blood; TCR repertoire in peripheral blood could be a biomarker of clinical outcomes for chemotherapy and immunotherapy . We predicted that the peripheral blood TCR repertoire and lymphocyte subsets reflect the immune status of patients with SCLC, and its dynamic changes can reflect immune status changes.…”

“…Many studies have shown that lymphocytes recognize the patient's unique mutations in the peripheral blood 15,16 ; TCR repertoire in peripheral blood could be a biomarker of clinical outcomes for chemotherapy and immunotherapy. [17][18][19] We predicted that the peripheral blood TCR repertoire and lymphocyte subsets reflect the immune status of patients with SCLC, and its dynamic changes can reflect immune status changes.…”