Correlation between peripheral CD8+PD-1+ T cells diversity, tumor mutation burden (TMB) and T cell clones with anti-PD-1 antibody treatment of lung cancer patients: TCR repertoire as a novel predictive biomarker.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e14041-e14041
Author(s):  
Seiji Matsumoto ◽  
Takaji Matsutani ◽  
Yoshiko Fujita ◽  
Kazutaka Kitaura ◽  
Yukio Nakamura ◽  
...  
Keyword(s):  
T Cells ◽  
Peripheral Blood ◽  
Predictive Biomarker ◽  
Shannon Index ◽  
Simpson Index ◽  
Tumor Mutation Burden ◽  
Repertoire Analysis ◽  
Mutation Burden ◽  
Tcr Repertoire ◽  
Tcr Diversity

e14041 Background: Anti-PD-1 antibodies (nivolumab) are effective in the treatment of many cancers. There is a demand for less invasive biomarkers. Peripheral and tumor CD8+PD-1+ T cells share neoantigen-specific T-cell receptors (TCRs), and are presumed to act as effector T cells with an antitumor effect at the tumor site. We analyzed the diversity in terms of TCR α and β repertoires on peripheral CD8+PD-1+ T cells, tumor mutation burden and examined the relationship between this diversity and therapeutic effect of nivolumab. Methods: This study used patients administered nivolumab after exhibiting no response to chemotherapy for recurrence following surgery. Peripheral blood mononuclear cells were collected from patients before administration of nivolumab. CD8+PD-1+ T cells were subjected to FACS sorting, NGS-based TCR repertoire analysis was performed by Repertoire Genesis Inc., and TCR diversity was evaluated statistically. This study was approved by the Ethical Committee of Hyogo College of Medicine. Results: Six of 12 patients responded to treatment. Upon comparing these responders (CR, PR) with non-responders (SD, PD), there were no differences in the proportion of PD-1+ in CD8+ T cells and the proportion of CD8+PD-1+ T cells in gated lymphocytes. TCR α diversity was significantly higher among responders than non-responders based on Shannon index, Simpson index and DE50 (P < 0.05, P < 0.05, P < 0.01, respectively). TCR β diversity was also significantly higher among responders than non-responders based on Shannon index, Simpson index and DE50 (all P < 0.01). Progression-free survival (PFS) was 371 days for responders and 148 days for non-responders. Overall survival (OS) was 633 days for responders and 308 days for non-responders, showing a significant difference between the groups. TCR repertoire was proportional to TMB. Clones found in multiple patients were more frequent in indel than in SNP. Conclusions: TCR repertoire analysis was performed on CD8+PD-1+ T cells in easily-obtainable peripheral blood before nivolumab treatment in patients with NSCLC, and nivolumab was observed to be effective in patients with high TCR diversity. This result indicates the TCR diversity of peripheral CD8+PD-1+ T cells is effective as a predictive biomarker for response to ICI therapy.

scholarly journals Tumor Mutation Burden: A Predictive Biomarker for Gastric Cancer Immunotherapy

2020 ◽  
Author(s):  
Renshen Xiang ◽  
Tao Fu
Keyword(s):  
Gastric Cancer ◽  
T Cells ◽  
Clinical Decision Making ◽  
Immune Cell ◽  
Predictive Biomarker ◽  
Clinical Decision ◽  
Tumor Mutation Burden ◽  
Follicular Helper ◽  
Tumor Purity ◽  
Mutation Burden

Abstract Background: Few studies have focused on the underlying relationship between the prognosis of tumor mutation burden (TMB) and immune cell infiltration in gastric cancer (GC). This study aims to explore the relationship among TMB and various components in tumor microenvironment (TME). Methods: The transcription profiles and somatic mutation data of 375 tumor and 32 normal samples were obtained from TCGA. The specific mutation information was summarized and visualized with waterfall chart, then number of TMB per million bases of each GC sample was calculated. Immune/stromal scores and tumor purity were calculated by the ‘ESTIMATE’ package, and the fractions of 22 immune cells in each sample were evaluated by CIBERSORT algorithm. Finally, Lass regression analysis was utilized to generate a prognostic scoring signature with TCGA cohort as the training set, while GES84437 cohort as the validation set. Results: Higher TMB indicated favorable overall survival (OS, P = 0.043)，better disease specific survival (P = 0.029), and longer progression free interval (P = 0.004). TMB was positively correlated with MSI and tumor purity, while negatively associated with immune/stromal scores. Moreover, TMBhigh group has lower T cells CD4 memory resting (P < 0.001) and T cells regulatory (P < 0.001), and more T cells CD4 memory activated (P < 0.001) and T cells follicular helper (P = 0.009). More importanly, the infiltration of dendritic cells activated predicted a worse OS, while T cells CD4 memory activated and T cells follicular helper meant a better OS. Finally, a nomogram combined TMB-related signature with clinicopathologic variables can successfully predict the OS with high accuracy and efficiency.Conclusion: TMB can effectively reveal the immune infiltration status in TME of GC, and might serve as a prognostic classifier for individualized treatment of clinical decision-making.

Activated and Expanded T Cells for Potential Therapy of Patients with Autoimmune Diseases.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 3854-3854
Author(s):  
Alice Long ◽  
Mark Bonyhadi ◽  
Christophe Ferrand ◽  
Mark Frohlich ◽  
Ronald J. Berenson
Keyword(s):  
T Cells ◽  
Immune System ◽  
T Cell ◽  
Side Effects ◽  
Autoimmune Diseases ◽  
Current Therapy ◽  
High Dose ◽  
Autoreactive T Cells ◽  
Repertoire Analysis ◽  
Tcr Repertoire

Abstract Autoreactive T cells have been implicated as central players in many autoimmune diseases. Current therapy for autoimmune diseases involves chronic immunosuppression, which increases the risk of infection and cancer, and is associated with other side effects. Recently, high-dose chemotherapy combined with stem cell transplantation has been used, but is often associated with severe toxicities. To avoid the side effects associated with these therapies, we are developing an alternative therapeutic approach in which patients are treated with relatively non-toxic therapy to reduce T cell numbers, and then administered healthy T cells to restore the immune system. Most autoimmune patients have oligoclonal populations of T cells as measured by T cell receptor (TCR) repertoire analysis. These may represent autoreactive T cells which contribute to TCR repertoire skewing. Clinical studies have shown a positive correlation between post-therapy TCR repertoire normalization and remission of autoimmune diseases. We have developed the Xcellerate™ Technology for the ex vivo activation and expansion of T cells. To expand T cells, peripheral blood mononuclear cells (PBMCs) are cultured with microscopic paramagnetic beads conjugated with anti-CD3 and anti-CD28 mAbs (Xcyte™Dynabeads®). T cells manufactured using this or a similar technology have been administered to patients with cancer and HIV in several clinical trials. In these studies, we and others have shown that the Xcellerate Technology can normalize skewed TCR repertoires in these patient populations. In the present study, we evaluated the use of the Xcellerate Technology to grow T cells from patients with autoimmune diseases such as rheumatoid arthritis, scleroderma, Crohn’s disease and systemic lupus erythematosus. We collected data on cytokine secretion, activation marker expression, cell expansion and TCR repertoire. T cells expanded an average of 1,325 fold (±1,592; range=16–6,532; n=35 patients), with nearly all cultures displaying marked CD25 and CD154 upregulation, and secretion of high levels of IFNγ and GM-CSF. Similar to results observed in cancer patients, TCR repertoire analysis showed that the Xcellerate Technology can normalize the skewed repertoires observed in autoimmune patients. Out of 12 PBMCs examined by spectratype analysis, one showed no TCR Vβ skewing prior to expansion, whereas the remaining 11 tissues displayed varying degrees of skewedness. After expansion, repertoire skewedness was decreased for all 11 samples. Repertoire normalization was dependent upon high-levels of TCR/CD28 engagement, which was achieved by initiating cultures using high bead to T cell ratios (Figure 1). Neither type of autoimmune disease, disease severity nor patient treatment (including: steroids, melphalan, infliximab, rapamycin, etc.) at the time of blood collection had an adverse effect on the ability to expand the patients’ T cells. Based on these results, the Xcellerate Technology may prove useful for generating healthy T cells from patients with autoimmune diseases which could then be used to restore the immune system following lymphoablative therapy. Studies are underway to further evaluate this approach. Figure Figure

Effect of anti-CTLA-4 antibody treatment on T-cell repertoire evolution in treated cancer patients.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 3020-3020
Author(s):  
Edward Cha ◽  
Yafei Hou ◽  
Mark Klinger ◽  
Craig Cummings ◽  
Malek Faham ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cancer Patients ◽  
Multiple Time ◽  
T Cell Repertoire ◽  
Cell Repertoire ◽  
Antibody Treatment ◽  
Tcr Repertoire ◽  
Tcr Diversity ◽  
Morisita Index

3020 Background: CTL-associated antigen 4 (CTLA-4) is an immune checkpoint expressed by T cells. While treatment with anti-CTLA-4 antibody can induce clinical responses in advanced cancer patients, its effects on the breadth of the T cell response is unknown. Methods: We used a sequencing-based method, LymphoSIGHT, to assess T cell repertoire diversity in 46 patients with metastatic castration resistant prostate cancer or metastatic melanoma. Peripheral blood mononuclear cells were obtained from patients prior to and during treatment with anti-CTLA-4 antibody. mRNA was amplified using locus-specific primer sets for T cell receptor (TCR) beta, and the amplified product was sequenced. Sequence reads were used to quantitate absolute TCR frequencies using standardized clonotype determination algorithms with normalization by spiked reference TCR sequences. Following clonotype quantitation, repertoire differences between serial samples were assessed by the Morisita index, a statistical measure of population dispersion. Results: 97 paired samples were assessed, of which 46 (47%) had increases and 22 (23%) had decreases in TCR diversity by more than 2-fold. By comparison, none of 9 untreated sample pairs underwent more than a 2-fold change in diversity (P = 0.005, Fisher’s exact test, two tailed). TCR repertoire differences between monthly samples were markedly higher than for time-matched controls. After the first treatment, median Morisita index between samples was 0.197 for treated samples versus 0.039 for untreated (P = 0.0005, Mann-Whitney U test). The median number of clones that significantly changed in abundance was 421 for treated versus 45 for controls. In patients with multiple time points, this rapid clonotype evolution continued through treatment. Despite this global turnover in repertoire, a subset of high frequency clones, including CMV-specific T cells, remained relatively constant over the course of the study. Conclusions: CTLA-4 blockade increases the global rate of T cell clonotype turnover and influences TCR diversity. This evolution of the TCR repertoire may reflect a mechanism by which CTLA-4 blockade enhances tumor-specific T cells over time.

Distinct contributions of CD4+ and CD8+naive and memory T-cell subsets to overall T-cell–receptor repertoire complexity following transplantation of T-cell–depleted CD34-selected hematopoietic progenitor cells from unrelated donors

Blood ◽  
2002 ◽  
Vol 100 (5) ◽  
pp. 1915-1918 ◽  
Author(s):  
Matthias Eyrich ◽  
Tanja Croner ◽  
Christine Leiler ◽  
Peter Lang ◽  
Peter Bader ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Progenitor Cells ◽  
T Cell Receptor ◽  
Peripheral Blood ◽  
Cell Receptor ◽  
T Cell Subsets ◽  
Memory T Cell ◽  
Tcr Repertoire ◽  
Unrelated Donors

Normalization of restricted T-cell–receptor (TCR) repertoire is critical following T-cell–depleted (TCD) stem cell transplantation. We present a prospective study analyzing respective contributions of naive and memory T-cell subsets within the CD4+ and CD8+ compartments to the evolution of overall TCR-repertoire complexity following transplantation of CD34-selected peripheral blood progenitor cells from unrelated donors. During the first year after transplantation, sorted CD4/45RA, CD4/45R0, CD8/45RA, and CD8/45R0 subsets were analyzed at 3-month intervals for TCR-repertoire complexity by CDR3 size spectratyping. Skew in TCR-repertoire was observed only in early memory-type T cells. CD4+ and CD8+ subsets differed in clonal distribution of CDR3 sizes, with rapid Gaussian normalization of bands in CD4/45R0+ T cells. Naive T cells displayed normal repertoire complexity and contributed significantly to skew correction. Our data provide direct evidence for an important role of de novo maturation of naive T cells in normalization of an initially restricted TCR-repertoire following transplantation of CD34-selected, TCD-depleted peripheral blood progenitors from unrelated donors.

scholarly journals The T-Cell Receptor Repertoire Predicts Interim-PET in Patients with DLBCL Treated with R-CHOP: An Observational Study from a Prospective Clinical Trial

Blood ◽  
2017 ◽  
Vol 130 (Suppl_1) ◽  
pp. 825-825
Author(s):  
Mohamed Shanavas ◽  
Mark Hertzberg ◽  
Rodney J Hicks ◽  
John F Seymour ◽  
Joshua W.D. Tobin ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Receptor ◽  
Peripheral Blood ◽  
T Cell Responses ◽  
Cell Receptor ◽  
Variable Degree ◽  
Cell Responses ◽  
Interim Pet ◽  
Tcr Repertoire

Abstract T-cell infiltration of the tumor microenvironment (TME) in DLBCL is a key determinant of response to chemo-immunotherapy (Keane, Lancet Haem 2015). We have previously shown that greater diversity of the T-cell receptor (TCR) repertoire within the TME is correlated with improved survival following R-CHOP in DLBCL (Keane, CCR 2017). There are limited data on the impact of the intratumoral TCR repertoire on interim-PET (iPET), the relationship between intratumoral and circulating TCRs, and on dynamic changes of the TCR during therapy. In this study, we interrogated the TCR repertoire in a subset of DLBCL patients treated on the prospective Australasian Leukaemia Lymphoma Group NHL21 study (Hertzberg, Haematologica 2017), in which all patients had 4x RCHOP prior to iPET risk stratification. The CDR3 region of TCRβ chain underwent high-throughput unbiased TCRβ sequencing (Adaptive Biotechnologies). Metrics included: productive templates (total functional T-cells), productive rearrangements (functional T-cells with distinct specificity), productive clonality (repertoire unevenness due to clonal expansions), and maximal frequency clones (% most dominant single clone). Matched intratumoral diagnostic samples, blood at pre-therapy and post-cycle 4 (at the time of iPET) were tested. 42 patients (enriched for iPET+ cases) had sufficient material for testing. Median age was 55 (range 22-69) years and 72% were males. IPI was low/intermediate/high in 13/63/25% respectively. Cell of origin (COO) by Lymph 2CX method (nanoString) was ABC in 30%, and GCB in 44%. 40% were iPET+. In tissue, there was a median of 4652 productive templates, translating into 2998 productive rearrangements identified. Notably, the clonal repertoire of intratumoral TCRs in iPET+ patients was larger than iPET-ve patients (productive clonality 8.1 vs 5.1 x10-2, p=0.04), whereas the numbers of functional T-cells did not vary between groups. Comparing the tumor with the blood samples showed a high, but variable, degree of overlap between peripheral blood and the TME - TCR repertoire. Median number of top 100 tumor tissue clones shared in peripheral blood was 53.5 (range, 1-97) in pre-therapy and 39.5 (range, 0-93) in post-therapy blood, indicating that the both the circulation and the tumor likely contribute to immune-surveillance. In pre-therapy blood, the median productive templates and productive rearrangements were 44,950 (range, 6,003-273,765) and 29,090 (range, 5,190-152,706), and the median clonality was 8.5 (1.46-45.3) x 10-2. There were no differences between iPET+ and iPET-ve patients in these parameters. However, there was a marked change in T-cell composition between time points. Interestingly, in iPET-ve patients clonality measures were increased, with productive clonality 9.4 vs 14.4 x10-2, p=0.03; and % maximum productive frequency 3.39 vs 5.89, p=0.04. These findings demonstrate that the intratumoral TCR repertoire, and sequential blood sampling provide important information on outcome in DLBCL treated with RCHOP. A highly clonal T-cell repertoire in the TME was associated with iPET positivity after 4 cycles of R-CHOP. In line with findings in solid cancers treated with checkpoint blockade, development of clonal responses in peripheral blood was associated with iPET negativity. These findings indicate that clones expanded during therapy may be important in tumor clearance but that highly clonal T-cell responses in the tumor at diagnosis may hinder expansion of other T-cell responses to neoantigens. The circulating TCR composition is representative of the TME. These findings will assist the rationale design and therapeutic monitoring of novel immuno-therapeutic strategies. Disclosures No relevant conflicts of interest to declare.

scholarly journals TCR Diversity Is a Predictive Marker for Donor Lymphocyte Infusion Response

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 4605-4605 ◽  
Author(s):  
Christian Schultze-Florey ◽  
Solaiman Raha ◽  
Sarina Ravens ◽  
Leonie Kuhlmann ◽  
Melanie Drenker ◽  
...  
Keyword(s):  
T Cells ◽  
Clinical Outcome ◽  
Research Funding ◽  
Remission Induction ◽  
Immunologic Response ◽  
Whitney Test ◽  
Mann Whitney Test ◽  
Cdr3 Region ◽  
Tcr Repertoire ◽  
Tcr Diversity

Abstract Background: Relapse of disease remains a frequent cause of mortality after allogeneic hematopoietic stem cell transplantation (HSCT). For patients with imminent relapse, therapeutic donor lymphocyte infusions (DLI) offer a treatment option for re-induction of complete remission of the underlying disease by employing the graft-versus-leukemia (GvL) effect. Moreover, DLI is used pre-emptively to prevent relapse in patients with high risk disease. DLI is given in increasing doses, adapted to clinical signs of graft-versus-host disease (GvHD) or molecular markers of disease, i.e. donor chimerism or minimal residual disease. There is a need for reliable monitoring of the immunologic response preceding the clinical outcome, enabling a precise administration of DLI dose escalation and thus possibly preventing overshooting immune reactions. With the advent of deep sequencing technology direct measure of high resolution T cell receptor (TCR) diversity can be used as a read-out of the immunologic response in the patient at the molecular level. Aims: In this study we aim to elucidate whether TCR-diversity can serve as a biomarker for clinical outcome of DLI treatment. Patients and Methods: We assessed 19 patients, who received DLI after HSCT. Therapeutic DLI was given in 14 patients and prophylactic DLI in 5 patients. The majority of patients (n=14) was treated for AML or MDS, 2 for ALL, and 3 for MPN. Peripheral blood samples for TCR-sequencing were obtained from the patient pre-DLI, at 2 and 4 weeks post DLI, and subsequently when available. Also, donor samples were collected. Donor's and patient's lymphocytes were FACS-sorted into CD8+ and CD4+ conventional (Tconv) and CD4+CD127-CD25+ regulatory T cells (Treg). Sorted subpopulations were subject to cDNA-based CDR3-region amplification by RACE-PCR allowing assessment of the entire TCR-β repertoire. Reliable generation of CDR3 amplicons was possible from as few as 4000 cells. These were then sequenced using the Illumina MiSeq platform. Reads were annotated by the IMGT.org database; further bioinformatics analyses included VDJtools and the tcR R-package. Results: GvL response (remission or stable disease) could be achieved in 14/19 patients; 8 of these patients developed acute GvHD ≥III°. Flow cytometric analysis showed that the ratio between CD8+ and CD4+ Tconv in the DLI is predictive of response to DLI: DLIs containing a majority of CD4+ Tconv were associated with development of GvHD (n=8, CD8:CD4 = 35.3%:54.9%) , whereas patients responding to DLI with GvL only had received a higher proportion of CD8+ T cells (n=6, CD8:CD4 = 59.1%:29.5%); comparison of ratios met statistical significance (Mann Whitney test, p=0.0027). TCR sequencing revealed that the diversity of the TCR-repertoire seems to be predictive of the clinical course of the patient after DLI. GvHD development within 2 weeks of blood sampling time (n=4) was preceded by an increase of Treg repertoire diversity (assessed with inverse Simpson's diversity index, 1/Ds). Compared to the pre-DLI repertoire 1/Ds, mean increase was 143.67% vs. a 36.04% decrease in patients not developing GvHD (n=7; Mann Whitney test, p=0.02). Steroid treatment of GvHD (n=2) led to a mean decrease of 49.71% of Treg TCR 1/Ds compared to the previous time point. Analysis of GvL response revealed an association of remission induction with a trend towards decreased 1/Ds of the CD8+ TCR-repertoire (mean decrease of 27.66% at d28 after DLI compared to pre-DLI vs. 0.31% decrease in patients showing no GvL effect). Assessment of TCR CDR3 region clonotype expansion over time is shown for a patient responding with GvHD (Fig. 1A) and GvL (Fig. 1C) to DLI and a patient progressing without response to DLI (no GvHD Fig. 1B, no GvL Fig. 1D). Conclusion: Our data indicate that TCR sequencing allows the assessment of TCR-diversity change as a surrogate parameter of DLI response. While an increase of Treg diversity seems to indicate the development of GvHD, repertoire compression of the CD8 compartment may be predictive of GvL response. Taken together, monitoring TCR repertoires may become a valuable predictive tool to improve DLI therapy and furthermore, analysis of expanding clonotypes after DLI enables identification of individual CDR3 sequences associated with DLI response. Disclosures Heuser: Pfizer: Research Funding; Novartis: Consultancy, Research Funding; BerGenBio: Research Funding; Karyopharm Therapeutics Inc: Research Funding; Tetralogic: Research Funding; Celgene: Honoraria; Bayer Pharma AG: Research Funding.

scholarly journals Integrative molecular profiling of autoreactive CD4 T cells in autoimmune hepatitis

2020 ◽  
Author(s):  
Amédée Renand ◽  
Iñaki Cervera-Marzal ◽  
Laurine Gil ◽  
Chuang Dong ◽  
Erwan Kervagoret ◽  
...  
Keyword(s):  
T Cells ◽  
Disease Activity ◽  
Autoimmune Hepatitis ◽  
Peripheral Blood ◽  
Cd4 T Cells ◽  
Ex Vivo ◽  
B Cell Differentiation ◽  
Tcr Repertoire ◽  
First Time

AbstractBackground & AimsIn most autoimmune disorders, crosstalk of B cells and CD4 T cells results in the accumulation of autoantibodies. In autoimmune hepatitis (AIH), the presence of anti-Soluble Liver Antigen (SLA or SepSecs) autoantibodies is associated with significantly reduced overall survival, but the associated autoreactive CD4 T cells have not been characterized yet. Here we isolated and deeply characterized SLA-specific CD4 T cells in AIH patients.MethodsWe used brief ex vivo restimulation with overlapping SLA-derived peptides to isolate and phenotype circulating SLA-specific CD4 T cells, and integrative single-cell RNA-seq (scRNA-seq) to characterize their transcriptome and TCR repertoire in n=5 AIH patients. SLA-specific CD4 T cells were tracked in peripheral blood through TCR sequencing, to identify their phenotypic niche. We further characterized disease-associated peripheral blood T cells by high content flow cytometry in an additional cohort of n=46 AIH patients and n=18 non-alcoholic steatohepatitis (NASH) controls.ResultsAutoreactive SLA-specific CD4 T cells were only detected in patients with anti-SLA autoantibodies and had a memory PD-1+CXCR5−CCR6−CD27+ phenotype. ScRNA-seq revealed their pro-inflammatory/B-Helper profile (IL21, IFNG, TIGIT, CTLA4, NR3C1, CD109, KLRB1 and CLEC2D). Autoreactive TCR clonotypes were restricted to the memory PD-1+CXCR5− CD4 T cells. This subset was significantly increased in the blood of AIH patients and supported B cell differentiation through IL-21. Finally, we identified a specific phenotype (PD-1+CD38+CD27+CD127−CXCR5−) of CD4 T cells linked to disease activity and IgG response during AIH.ConclusionsThis work provides for the first time a deep characterization of rare circulating autoreactive CD4 T cells and the identification of their peripheral reservoir in AIH. We also propose a generic phenotype of pathogenic CD4 T cells related to AIH disease activity.

scholarly journals Defining muscle-invasive bladder cancer immunotypes by introducing tumor mutation burden, CD8+ T cells, and molecular subtypes

Hereditas ◽  
2021 ◽  
Vol 158 (1) ◽  
Author(s):  
Zihao Chen ◽  
Guojun Liu ◽  
Guoqing Liu ◽  
Mikhail A. Bolkov ◽  
Khyber Shinwari ◽  
...  
Keyword(s):  
Bladder Cancer ◽  
T Cells ◽  
Signaling Pathway ◽  
Cd8 T Cells ◽  
Molecular Subtypes ◽  
Molecular Subtype ◽  
Muscle Invasive Bladder Cancer ◽  
Tumor Mutation Burden ◽  
Mutation Burden ◽  
Muscle Invasive

AbstractImmunotherapy, especially anti-PD-1, is becoming a pillar of modern muscle-invasive bladder cancer (MIBC) treatment. However, the objective response rates (ORR) are relatively low due to the lack of precise biomarkers to select patients. Herein, the molecular subtype, tumor mutation burden (TMB), and CD8+ T cells were calculated by the gene expression and mutation profiles of MIBC patients. MIBC immunotypes were constructed using clustering analysis based on tumor mutation burden, CD8+ T cells, and molecular subtypes. Mutated genes, enriched functional KEGG pathways and GO terms, and co-expressed network-specific hub genes have been identified. We demonstrated that ORR of immunotype A patients identified by molecular subtype, CD8+ T cells, and TMB is about 36% predictable. PIK3CA, RB1, FGFR3, KMT2C, MACF1, RYR2, and EP300 are differentially mutated among three immunotypes. Pathways such as ECM-receptor interaction, PI3K-Akt signaling pathway, and TGF-beta signaling pathway are top-ranked in enrichment analysis. Low expression of ACTA2 was associated with the MIBC survival benefit. The current study constructs a model that could identify suitable MIBC patients for immunotherapy, and it is an important step forward to the personalized treatment of bladder cancers.

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