Hematological Cancer Patients Research Articles

Background: Relapse is the major treatment failure of allogeneic hematopoietic stem cell transplantation (HSCT) in patients with hematologic malignancies. Especially, early relapse had seriously bad prognosis. And tumor-infiltrating T cells play an important role in disease progression and recurrence. However, there is lack of data about the marrow-infiltrating T cell of early relapsed patients compared to those with complete remission (CR) at an early timepoint after HSCT. Therefore, we analyzed the differentiation stage and expression of inhibitory receptors of the marrow-infiltrating T cell in the early stages of allogeneic HSCT. Method: A total of 40 samples from patients treated at Chungnam National University Hospital were collected between April 2021 and October 2022. We used flow cytometry to classify T cells into five subtypes using CD45RA, CD95, and CCR7: naïve, stem cell memory (SCM), central memory (CM), effector memory (EM) and effector memory with positive CD45RA (EMRA). Otherwise, we analyzed regulatory T cell (Treg) by defining as CD25 highCD127 low and divided them into three categories using CD25 and CD45RA: naïve, active and non-suppressive Treg. We defined early relapse (ER) as relapse within 6 months of allogeneic HSCT. High-throughput single-cell RNAseq assays from BM lymphocytes isolated by density gradients were performed to determine the expression and cell composition of previously irradiated markers. Results: With this approach, marrow-infiltrating T cells were analyzed in 40 patients (10 patients with early relapse) with a median age of 57 years (ranged from 30 to 71). AML is the most common disease at 60%, followed by MDS (20%), ALL (15%) and PMF (2.5%). Stem cell sources were 32.5% from matched sibling donor, 37.5% from haplo-identical donor and 27.5% from matched unrelated donor. All patients received mobilized peripheral blood stem cell transplantation. Marrow-infiltrating CD3+T cell counts were lower in patients with allogeneic HSCT compared to normal subjects (CD3+T cells: 13.89% in HSCT patient and 9.116% in ER patients vs. 34.19% in normal subjects, p&lt; 0.0001). In addition, CD3+CD8+T cells were higher in CR than ER patients (CD3+CD8+T cells: 50.39% in CR vs. 30.41% in ER patients, p&lt; 0.0033). In HSCT patients, naïve was higher, and EM and EMRA were lower than those in normal subjects among CD4+T cells (naïve; 8.629% in ER patients and 5.119% in CR patient's vs 45.76% in normal subjects, p&lt; 0.0001/EM; 54.04% in ER patients and 55.93% in CR patients vs 18.61 in normal subject, p= 0.0003 and p&lt; 0.0001 respectively). Of CD3+T cells, the proportion and expression level of TIM-3 was higher ER patients than in CR patients (56.33% in ER patients vs 39.20% in CR patients, p= 0.0185/MFI; 1873 in ER patients vs. 826.7 in CR patients, p= 0.0331). Of CD4+T cells, the percentage of TIM-3 was lower in normal subjects than in allogeneic HSCT patients (7.794% in normal vs 30.11% in CR patients and 26.04% in ER patients, p= 0.0002 and p= 0.0102 respectively). In patients with ER, naïve and EM was higher than those in CR patients among CD8+T cells (naïve; 8.680% in ER patients vs 4.066% in CR patients, p= 0.4001 /EM; 54.44% in ER patients vs 44.33% in CR patients, p= 0.3039). Of CD8+ EMRA T cell, the expression of TIM-3 was higher in ER patients than in CR patients (MFI; 1441 in HSCT patients vs 421.7 in normal, p=0.1038). Otherwise, of CD3+CD4-CD8-, The percentage of TIM3 was higher in ER patients than CR patients (80.33 % in ER patients vs 62.49% in CR patients, p= 0.0333). Treg levels were no significant difference between CR and ER. We have obtained single-cell sequencing data from two CR (complete response) patients and two ER (early relapse) patients, representing each group. Since the classified groups exhibited ambiguous phenotypes, they were reclassified based on specific markers of cell groups. The reclassified groups showed a higher proportion of HCS (Hematopoietic Stem Cell)-like cells in relapsed patients (+10.14%, P=0.368) and a lower proportion of CD8+ T cells (-13.40%, p=0.068). The HSC-like cells in relapsed patients exhibited higher expression of TIM3 ligand than in CR patients Conclusion: Among the IRs, TIM3 had the highest expression of all cell groups (CD4 T cells, CD8 T cells and Treg) compared with other IRs at the early stage of allogeneic HSCT. So, TIM3 might be a potential target for preventing relapse in hematologic cancer patients after allogeneic HSCT in the future.

T cell receptors (TCRs) play a crucial role in orchestrating cellular immunity in both health and disease, particularly in the context of cancer. Although immunotherapy and stem cell transplantation have shown promising clinical responses in hematological malignancies, these have not been linked to the presence of endogenous tumor reactive T cells. Moreover, the specificities and phenotypes of such tumor recognizing TCRs in these largely low immunogenic entities are unknown. In this study, we addressed this gap by developing an approach to map TCR specificities and transcriptional phenotypes of human bone marrow-resident T cells directly ex vivo, focusing on patients who were treatment-naïve at the time of biopsy. This allowed us to generalize our findings beyond immune checkpoint inhibitor-treated patients, a limitation of previous studies in solid cancers. To discover T cells that specifically recognize cancer cells or viral epitopes, we developed a multiplexed profiling approach using microfluidic reaction chambers, optical cytokine detection and TCR sequencing of patient-derived primary T cells. We were able to confidently map TCR recognition of 25,957 bone marrow-resident T cells from n=20 hematological cancer patients. Based on the acquired functional data and reverse phenotyping of screened TCRs to their original cell state in situ, we built a bone marrow T cell atlas charting &gt;300,000 expression profiles in human bone marrow-resident T cells, their TCR specificities as well as their longitudinal clonal dynamics upon therapeutic perturbations in n=40 patients with newly diagnosed multiple myeloma (MM) and acute myeloid leukemia (AML). Our approach detected tumor-reactive T cell clones in the bone marrow of all screened individuals with varying frequency (1-5% of T cells), which were largely found to display a CD8+ effector-memory or progenitor-exhausted phenotype. In contrast, non-tumor reactive clones were either CD4+ or enriched for viral specificities. We identified a conserved signature of anti-tumor reactivity across patients. This signature included the ITGB1 gene, which encodes CD29 and was uniformly expressed in tumor reactive T cells. Importantly, ITGB1 expression was specifically restricted to tumor reactive, compared to virus-specific or bystander T cells. In two independent mouse tumor models, we found that CD29 protein was significantly upregulated on homed T cells carrying tumor reactive TCRs compared to non-reactive TCRs. A causal link between tumor reactive T cells and clinical response to hematological cancers would be strengthened by finding that these cells specifically recognize autologous cancer epitopes and clonally expand as part of a clinical anti-tumor response. We therefore cloned patient-individualized TCR libraries and performed immunoprecipitation of MHC class I : peptide complexes from cancer cells. We validated TCR binding against ~1-20 epitopes per patient, which were mostly derived from cancer/testis antigens (CTAs) and novel open reading frames (nORFs). Finally, we classified tumor reactive TCRs in three clinical cohorts: Notably, we observed selective expansion of tumor reactive TCRs upon autologous stem cell transplantation, which was associated with deep clinical response in newly diagnosed MM patients. Conversely, the failure of tumor reactive TCRs to clonally expand on-treatment underlined clinical non-response to bispecific BCMAxCD3 antibody therapy (MM) or combination therapy with immune checkpoint inhibitors and Azacytidine (AML). We show here that, unexpectedly, clinically relevant endogenous anti-tumor reactivity lies in a rare subset of bone marrow-resident T cells. The recurrent detection of these immunotherapy-responsive TCRs in patients with MM or AML revealed the selective clonal expansion of tumor-reactive TCRs following autologous stem cell transplantation. We describe a conserved gene signature of tumor reactivity that diverges from lymphocytes infiltrating solid tumors and includes CD29 as an indicator of antigen-specific T cell homing. Our findings facilitate the antigen-agnostic identification of tumor-reactive TCRs with potential for future patient-individualized cell therapies and suggest the relevance of immune responses against alternative epitopes, such as cancer/testis antigens, in hematological malignancies with low mutational loads.

Hematological Cancer Patients Research Articles

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