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Besides chemotherapy and hematopoietic stem cell transplantation (HSCT), autologous T cells can also serve as a new treatment approach for AML patients. However, the features of tumor-reactive T cells and their distinctive markers still lack full description. To evaluate the characteristics of tumor-reactive T cells, we collected bone marrow (BM) T cells from newly diagnosed AML patients with RUNX1::RUNX1T1 as examples for paired single-cell RNA sequencing and single-cell V(D)J sequencing. Based on the STARTRAC-like algorithm, we defined bystander T cells and tumor-reactive T cells. Compared with bystander T cells, tumor-reactive T cells presented as senescent-like cytotoxic terminally differentiated T cells (Temra) with upregulated NK-related markers. Additionally, we found ADGRG1 could serve as the specific marker of CD8+ T tumor-reactive T cell and validated it through the Runx1Runx1t1/+; Mx1-Cre mouse model. In chimeric antigen receptor (CAR)-T and target cell system, ADGRG1 was selectively upregulated upon antigen-TCR encounter. Moreover, ADGRG1+CD8+ T cells released a higher level of IFN-γ and showed higher cell-killing ability when exposed to matched AML blasts. Together, our findings depict the single-cell profile of tumor-reactive T cells in AML BM and propose that ADGRG1 can act as an indicator of T cell tumor reactivity in AML, which may be further harnessed for adoptive cell therapy and tumor-reactive TCR enrichment. Key points: 1. CD8+ tumor-reactive T cells present in AML BM and are characterized as senescent-like cytotoxic Temra with upregulated NK-related markers. 2. ADGRG1 can serve as a specific marker of CD8+ tumor-reactive T cells in AML BM. [ABSTRACT FROM AUTHOR]

Abstract Besides chemotherapy and hematopoietic stem cell transplantation (HSCT), autologous T cells can also serve as a new treatment approach for AML patients. However, the features of tumor-reactive T cells and their distinctive markers still lack full description. To evaluate the characteristics of tumor-reactive T cells, we collected bone marrow (BM) T cells from newly diagnosed AML patients with RUNX1::RUNX1T1 as examples for paired single-cell RNA sequencing and single-cell V(D)J sequencing. Based on the STARTRAC-like algorithm, we defined bystander T cells and tumor-reactive T cells. Compared with bystander T cells, tumor-reactive T cells presented as senescent-like cytotoxic terminally differentiated T cells (Temra) with upregulated NK-related markers. Additionally, we found ADGRG1 could serve as the specific marker of CD8+ T tumor-reactive T cell and validated it through the Runx1Runx1t1/+; Mx1-Cre mouse model. In chimeric antigen receptor (CAR)-T and target cell system, ADGRG1 was selectively upregulated upon antigen-TCR encounter. Moreover, ADGRG1+CD8+ T cells released a higher level of IFN-γ and showed higher cell-killing ability when exposed to matched AML blasts. Together, our findings depict the single-cell profile of tumor-reactive T cells in AML BM and propose that ADGRG1 can act as an indicator of T cell tumor reactivity in AML, which may be further harnessed for adoptive cell therapy and tumor-reactive TCR enrichment.

Homologous recombination deficiency (HRD) is prevalent in cancer, sensitizing tumor cells to poly (ADP-ribose) polymerase (PARP) inhibition. However, the impact of HRD and related therapies on the tumor microenvironment (TME) remains elusive. Our study generates single-cell gene expression and T cell receptor profiles, along with validatory multimodal datasets from >100 high-grade serous ovarian cancer (HGSOC) samples, primarily from a phase II clinical trial (NCT04507841). Neoadjuvant monotherapy with the PARP inhibitor (PARPi) niraparib achieves impressive 62.5% and 73.6% response rates per RECIST v.1.1 and GCIG CA125, respectively. We identify effector regulatory T cells (eTregs) as key responders to HRD and neoadjuvant therapies, co-occurring with other tumor-reactive T cells, particularly terminally exhausted CD8+ T cells (Tex). TME-wide interferon signaling correlates with cancer cells upregulating MHC class II and co-inhibitory ligands, potentially driving Treg and Tex fates. Depleting eTregs in HRD mouse models, with or without PARP inhibition, significantly suppresses tumor growth without observable toxicities, underscoring the potential of eTreg-focused therapeutics for HGSOC and other HRD-related tumors. [Display omitted] • The TME of HRD HGSOC is characterized by the enrichment of tumor-reactive T cells • Neoadjuvant therapies preferentially suppress infiltrating eTregs in HRD tumors • TME-wide interferon signaling correlates with HRD-dependent eTreg enrichment • Joint targeting of PARP and eTregs in HRD tumors exhibits superior therapeutic efficacy Examination of tumor microenvironment dynamics following neoadjuvant PARP inhibition or chemotherapy in newly diagnosed high-grade serous ovarian cancers (HGSOCs) reveals effector Treg cells (eTregs) as a major mediator of homologous recombination deficiency (HRD) and treatment effects. Depletion of eTregs is shown to be effective in suppressing HRD tumors in multiple mouse models. [ABSTRACT FROM AUTHOR]

Tumor cells commonly express several antigens, such as tumor-associated antigens (TAAs) or mutation-derived antigens (neoantigens), that can be regarded as foreign antigens and elicit antitumor immune responses in cancer patients. Various TAAs or neoantigens expressed in cancer cells have been identified and utilized as targets for cancer vaccines. One approach to elicit tumorspecific immune responses is termed peptide-based cancer vaccination; it involves administrating TAAs or neoantigen-derived peptide for treatment of cancers. There have been several forms of peptide-based cancer vaccines depending on which effector cells, such as CTLs or CD4+ T-helper cells, are targeted to be activated. Many phase I and II clinical trials of peptide-based cancesr vaccines using TAA-derived CTL epitopes, T-helper cell epitopes or dendritic cells loaded with TAA-derived peptides for various malignant tumors have been conducted and provide clinical benefits in a small fraction of patients. Nowadays, to improve the efficiency of peptide-based cancer vaccines, combination immunotherapy of peptide-based cancer vaccines with the immunecheckpoint blockade therapies using mAbs specific for CTLA-4, programmed cell death 1 (PD-1), or PD-1 ligand 1 (PD-L1) have been developed for clinical application. Furthermore, along with the recent technological progress in genetic and bioinformatic analysis, it has become easier to identify neoantigens from individual cancer patients. It is expected that peptide-based cancer vaccines targeting neoantigens as a personalized cancer immunotherapy will be developed. [ABSTRACT FROM AUTHOR]

Tumor cells commonly express several antigens, such as tumor-associated antigens (TAAs) or mutation-derived antigens (neoantigens), that can be regarded as foreign antigens and elicit anti-tumor immune responses in cancer patients. Various TAAs or neoantigens expressed in cancer cells have been identified and utilized as targets for cancer vaccines. One approach to elicit tumor-specific immune responses is termed peptide-based cancer vaccination; it involves administrating TAAs or neoantigen-derived peptide for treatment of cancers. There have been several forms of peptide-based cancer vaccines depending on which effector cells, such as CTLs or CD4(+) T-helper cells, are targeted to be activated. Many phase I and II clinical trials of peptide-based cancer vaccines using TAA-derived CTL epitopes, T-helper cell epitopes or dendritic cells loaded with TAA-derived peptides for various malignant tumors have been conducted and provide clinical benefits in a small fraction of patients. Nowadays, to improve the efficiency of peptide-based cancer vaccines, combination immunotherapy of peptide-based cancer vaccines with the immune-checkpoint blockade therapies using mAbs specific for CTLA-4, programmed cell death 1 (PD-1), or PD-1 ligand 1 (PD-L1) have been developed for clinical application. Furthermore, along with the recent technological progress in genetic and bioinformatic analysis, it has become easier to identify neoantigens from individual cancer patients. It is expected that peptide-based cancer vaccines targeting neoantigens as a personalized cancer immunotherapy will be developed., (© The Japanese Society for Immunology. 2016. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)