scholarly journals Bystander CD4+ T cells infiltrate human tumors and are phenotypically distinct

2020 ◽  
Author(s):  
Yannick Simoni ◽  
Shamin Li ◽  
Summer Zhuang ◽  
Antja Heit ◽  
Si-Lin Koo ◽  
...  
Keyword(s):  
T Cells ◽  
Ex Vivo ◽  
Tumor Infiltrating Lymphocytes ◽  
Treg Cells ◽  
Immune Checkpoint Blockade ◽  
Mass Cytometry ◽  
Single Cell Sequencing ◽  
Protein Levels ◽  
Cancer Types ◽  
Infiltrating Lymphocytes

AbstractTumor-specific T cells likely underpin effective immune checkpoint-blockade therapies. Yet, most studies focus on Treg cells and CD8+ tumor-infiltrating lymphocytes (TILs). Here we study CD4+ TILs in human lung and colorectal cancers and observe that non-Treg CD4+ TILs average more than 70% of total CD4+ TILs in both cancer types. Leveraging high dimensional analyses including mass cytometry and single-cell sequencing, we reveal that CD4+ TILs are heterogeneous at both gene and protein levels, within each tumor and across patients. Consistently, we find different subsets of CD4+ TILs showing characteristics of effectors, tissue resident memory (Trm) or exhausted cells (expressing PD-1, CTLA-4 and CD39). In both cancer types, the frequencies of CD39− non-Treg CD4+ TILs strongly correlate with frequencies of CD39− CD8+ TILs, which we and others have previously shown to be enriched for cells specific for cancer-unrelated antigens (bystanders). Ex-vivo, we demonstrate that CD39− CD4+ TILs can be specific for cancer unrelated antigens, such as HCMV epitopes. Overall, our findings highlight that CD4+ TILs cells are not necessarily tumor-specific and suggest measuring CD39 expression as a straightforward way to quantify or isolate bystander CD4+ T cells.Graphical abstract

Prolongation of survival following depletion of CD4+CD25+ regulatory T cells in mice with experimental brain tumors

2006 ◽  
Vol 105 (3) ◽  
pp. 430-437 ◽  
Author(s):  
Abdeljabar El Andaloussi ◽  
Yu Han ◽  
Maciej S. Lesniak
Keyword(s):  
Immune Response ◽  
T Cells ◽  
Brain Tumors ◽  
Malignant Gliomas ◽  
Tumor Infiltrating Lymphocytes ◽  
Treg Cells ◽  
Separate Experiment ◽  
The Central Nervous System ◽  
Novel Target ◽  
Infiltrating Lymphocytes

Object Regulatory CD4+CD25+ T cells have been shown to play an important role in the regulation of the immune response. Whereas the presence of these cells has been associated with immune suppression, the lack of regulatory T (Treg) cells has been shown to induce autoimmunity. The purpose of this study was to define the role of Treg cells in tumors of the central nervous system (CNS). Methods The authors implanted syngeneic GL261 tumor cells in the brains or flanks of C57BL/6 mice. The resulting tumors were later removed at specific time points, and the presence of tumor-infiltrating lymphocytes was analyzed by performing flow cytometry for the presence of Treg cells. In a separate experiment, mice with GL261 tumors were treated with injections of anti-CD25 monoclonal antibody (mAb) to determine whether depletion of Treg cells may have an impact on the length of survival in mice with brain tumors. Tumor-infiltrating lymphocytes isolated from mice with GL261 tumors were found to have a significant increase in the presence of Treg cells compared with control lymphocytes (p < 0.05). Moreover, Treg cells isolated in murine brain tumors expressed FoxP3, CTLA-4, and CD62L. Mice treated with anti-CD25 mAb lived significantly longer than tumor-bearing control animals (p < 0.05). An analysis of brains in surviving animals showed a depletion of CD4+CD25+ T cells. Conclusions The results of this study indicate that CD4+CD25+ Treg cells play an important role in suppressing the immune response to CNS tumors. These Treg cells may therefore represent a potentially novel target for immunotherapy of malignant gliomas.

Association of KMT2C/D loss-of-function mutations with tumor infiltrating lymphocytes and response to immune checkpoint inhibitors in solid tumors.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 2587-2587
Author(s):  
Ruiqi Liu ◽  
Yanling Niu ◽  
Xin Zhang ◽  
Tonghui Ma
Keyword(s):  
Gene Expression ◽  
Colorectal Cancer ◽  
T Cells ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Tumor Infiltrating Lymphocytes ◽  
Loss Of Function ◽  
Cancer Types ◽  
Immune Related Genes ◽  
Infiltrating Lymphocytes

2587 Background: Dysregulation of HMTs plays an important role in tumorigenesis. KMT2C and KMT2D are enzymatically active scaffold proteins that form the core of mammalian COMPASS complexes, which methylate the histone 3 lysine 4. Both KMT2C and KMT2D are involved in the regulation of gene expression. Therefore, we explored the associations of KMT2C/D loss-of-function (LOF) mutations with the expression of immune-related genes, the levels of tumor infiltrating lymphocytes (TILs), and response to immune checkpoint inhibitors (ICIs). Methods: KMT2C/D LOF mutations were defined as nonsense, frameshift, splice site variants within consensus regions, start lost, and stop lost/gained variants. An ICIs treatment cohort from the MSKCC was used for exploring the associations between KMT2C/D LOF mutations and ICIs efficacy. The RNA-Seq data obtained from the TCGA cohort was used for analysis of gene expression and the levels of TILs using CIBERSORT. Results: In MSKCC pan-cancer dataset, patients with KMT2C/D LOF mutations had a relatively longer median overall survival (OS) compared to those with non-LOF mutations, although the result did not reach statistical significance (P = 0.0832). Then we analyzed the predictive roles of KMT2C/D LOF mutations for each cancer type. The results showed that the predictive role of KMT2C/D LOF mutations for the clinical efficacy of ICIs therapy was only observed in colorectal cancer (P = 0.045). However, we did not find the associations of KMT2C/D LOF mutations with ICIs efficacy in bladder cancer, breast cancer, melanoma, glioma, head and neck cancer, renal cell carcinoma, NSCLC, and esophagogastric cancer. Consistently, analysis of TILs in colorectal cancer revealed that KMT2C/D LOF was associated with increased infiltration of several types of immune cells, such as CD8+ T cells (P = 0.0001), activated NK cells (P = 0.0001), M1 macrophage (P = 0.0005), M2 macrophage (P = 0.0115), and neutrophils (P = 0.0209). Meanwhile, regulatory T cells (Tregs) (P = 0.0048) and M0 macrophage (P = 0.0043) were dramatically decreased in KMT2C/D LOF group for colorectal cancer. Moreover, there were no significant relationships between KMT2C/D LOF and the levels of TILs in other cancer types. Our data also demonstrated that KMT2C and KMT2D could regulate the expression of more than 30 immune-related genes in colorectal cancer. Conclusions: Our data indicated that KMT2C/D LOF mutations were significantly correlated with better outcomes of ICIs therapy in colorectal cancer, suggesting it can be as a useful predictor for response to ICIs in colorectal cancer. Meanwhile, we found the associations of KMT2C/D LOF with the levels of TILs in colorectal cancer, but not in other cancer types, indicating that the efficacy of ICIs was consistent with the levels of TILs.

503 Tumor infiltrating lymphocytes in soft tissue sarcomas upregulate the exhaustion marker TIGIT and are reinvigorated by IL-15 stimulation and TIGIT blockade

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A538-A538
Author(s):  
Sean Judge ◽  
Morgan Darrow ◽  
Steven Thorpe ◽  
Alicia Gingrich ◽  
Edmond O’Donnell ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Soft Tissue ◽  
Ex Vivo ◽  
Soft Tissue Sarcomas ◽  
Tumor Infiltrating Lymphocytes ◽  
Cd8 T Cell ◽  
Cell Phenotype ◽  
And Function ◽  
Infiltrating Lymphocytes

BackgroundAlthough the presence and activity of tumor infiltrating lymphocytes (TILs) have been shown to be important factors for survival and response to immunotherapy for multiple cancer types, the benefits of immunotherapy in soft tissue sarcomas (STS) have been limited, and novel approaches are needed. In this study, we sought to characterize the phenotype and function of tumor infiltrating natural killer (NK) and T cells in STS patients and to evaluate clinically relevant strategies to augment TIL function.MethodsUsing both prospectively collected blood and tumor tissue from STS patients undergoing surgical resection (n = 21) and archived specimens (n = 45), we performed flow cytometry and immunohistochemistry to evaluate the extent of peripheral and intratumoral CD3-CD56+ NK and CD8+ T cell phenotype and function as predictors of outcome. We also analyzed TCGA data and the peripheral blood of dogs with spontaneous osteosarcoma receiving inhaled IL-15 on a clinical trial to evaluate the association of CD3-NKp46+ NK and CD8+ T cell activation as well as TIGIT upregulation with outcome. Finally, we stimulated patient PBMCs and TILs ex vivo with IL-15 and a novel human anti-TIGIT antibody to assess the impact of combination therapy on NK and T cell phenotype and function. Parametric and non-parametric statistical tests were used where appropriate. Univariate and multivariate survival analyses were performed by Cox proportional hazards models.ResultsCompared to peripheral expression, intratumoral NK and T cells showed an activated and exhausted phenotype by CD69 and TIGIT, respectively. Ex vivo TIL stimulation with IL-15 further increased markers of activation and function including CD69, Ki67, IFNg, and granzyme B, while increasing expression of exhaustion marker TIGIT. Analysis of a retrospective STS cohort and TCGA STS gene expression confirmed the association of TILs with improved prognosis. Dogs with metastatic osteosarcoma receiving inhaled IL-15 exhibited upregulation of activation markers and TIGIT. In vitro, IL-15 and TIGIT blockade of both peripheral and intratumoral NK cells increased cytotoxicity against sarcoma cell lines and increased expression of degranulation marker CD107a compared to IL-15 alone.ConclusionsTILs are associated with improved survival in STS, and tumor infiltrating NK and T cells show features of both increased activation and increased exhaustion. Tumor-infiltrating NK and T cells respond to IL-15 stimulation, but simultaneously further upregulate TIGIT with the combination of IL-15 and TIGIT blockade showing greatest cytotoxic effects. Overall, our data suggest that the combination of IL-15 and TIGIT blockade is a promising clinical strategy in STS.Ethics ApprovalAll experiments involving human and canine patients were approved by the respective Institutional Review Boards at the University of California, Davis, Schools of Medicine (Protocol #218204-9) and Veterinary Medicine (IACUC #20179).

scholarly journals 64 A cloning and expression system of the neoantigen-specific TCRs from tumor-infiltrating lymphocytes by single-cell sequencing of paired TCRα and TCRβ chains

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A71-A71
Author(s):  
Yukari Kobayashi ◽  
Koji Nagaoka ◽  
Kaori Kubo ◽  
Toshikazu Nishie ◽  
Sachiko Okamoto ◽  
...  
Keyword(s):  
Lung Cancer ◽  
T Cells ◽  
Single Cell ◽  
Expression System ◽  
Tumor Infiltrating Lymphocytes ◽  
Cloning And Expression ◽  
Class I ◽  
Autologous Tumor ◽  
Single Cell Sequencing ◽  
Infiltrating Lymphocytes

BackgroundT-cells that target tumor neoantigens arising from cancer mutations are the primary mediators of cancer immunotherapies. Identifying neoantigens and T-cells that recognize them is essential for T-cell-based immunotherapy. However, neoantigen-reactive Tumor-infiltrating lymphocytes (TILs) are highly differentiated or exhausted with a limited proliferative capacity; it is challenging to expand them for a sufficient number to probe their specificity. Therefore, we developed a novel cloning and expression system to examine TCRs discovered by single-cell sequencing of TILs for their neoantigen-specificity.MethodsTILs of lung cancer and sarcoma were analyzed. Surgically removed tumors were divided into several pieces. They were enzymatically digested to prepare fresh tumor digest (FTD) and cryopreserved. They were used to generate TIL cultures and perform WES and RNA-Seq to identify tumor-specific mutations. MHCflurry was used to predict the binding affinity of potential epitopes arising from these mutations to HLA class I. Peptides that were predicted to bind to patients‘ own MHC class I molecules strongly were then synthesized. Single TILs isolated with the ICELL8® cx system (Takara Bio) were dispensed into a nanowell TCR chip containing preprinted barcodes. Barcoded cDNAs were PCR-amplified in-chip, pooled off-chip, and used as a template in the TCR-specific PCR or for the whole transcriptome library generation of 5’ ends of all transcripts. Based on single-cell transcriptome data and TCR profiles of TILs, we predict and prioritize neoantigen-specific TCRs and cloned them into siTCR® retrovirus vectors. These TCRs were transduced into SUP-T1-based reporter cells in which ZsGreen fluorescent protein expression is controlled by AP-1 and NFAT binding sites. TCR-expressing reporter cells were cocultured with patient autologous APCs pulsed with a pool of candidate neoantigen peptides. ZsGreen expression indicates that TCRs match their cognate neoantigens.ResultsIn a lung cancer patient, we set up 18 TIL cultures and obtained 12 TILs. TILs were cocultured with FTD; IFN-γ production was measured by ELISA to evaluate their reactivity to the autologous tumor. NGS identified 197 somatic mutations, 4 fusion genes, and 8 highly expressed cancer-testis antigens. Among them, 339 candidate peptides were synthesized and screened. In addition, we cloned 3 pairs of TCRαβ chains from most expanded TIL cultures and 4 TCRs from ex vivo TILs with exhausted phenotype. Two reporter cells that express TCRs from exhausted TILs responded to the same neoantigen peptide.ConclusionsGenerating TCR expressing cell lines facilitated the identifying neoantigens and their cognate TCR sequences from patients.Ethics ApprovalG3545

scholarly journals Combinatorial immunotherapy induces tumor-infiltrating CD8+ T cells with distinct functional, migratory, and stem-like properties

2021 ◽  
Vol 9 (12) ◽  
pp. e003614
Author(s):  
Natalija Van Braeckel-Budimir ◽  
Joseph Samuel Dolina ◽  
Jie Wei ◽  
Xiao Wang ◽  
Shih-Hsun Chen ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Single Agent ◽  
Tumor Infiltrating Lymphocytes ◽  
Immune Checkpoint Blockade ◽  
Tumor Rejection ◽  
Cell Subpopulation ◽  
Ki 67 ◽  
Combinatorial Immunotherapy ◽  
Infiltrating Lymphocytes

BackgroundProgrammed death (ligand) 1 (PD-(L)1) blockade and OX40/4-1BB costimulation have been separately evaluated in the clinic to elicit potent antitumor T cell responses. The precise mechanisms underlying single agent activity are incompletely understood. It also remains unclear if combining individual therapies leads to synergism, elicits novel immune mechanisms, or invokes additive effects.MethodsWe performed high-dimensional flow cytometry and single-cell RNA sequencing-based immunoprofiling of murine tumor-infiltrating lymphocytes (TILs) isolated from hosts bearing B16 or MC38 syngeneic tumors. This baseline infiltrate was compared to TILs after treatment with either anti-PD-(L)1, anti-OX40, or anti-4-1BB as single agents or as double and triple combinatorial therapies. Fingolimod treatment and CXCR3 blockade were used to evaluate the contribution of intratumoral versus peripheral CD8+ T cells to therapeutic efficacy.ResultsWe identified CD8+ T cell subtypes with distinct functional and migratory signatures highly predictive of tumor rejection upon treatment with single agent versus combination therapies. Rather than reinvigorating terminally exhausted CD8+ T cells, OX40/4-1BB agonism expanded a stem-like PD-1loKLRG-1+Ki-67+CD8+ T cell subpopulation, which PD-(L)1 blockade alone did not. However, PD-(L)1 blockade synergized with OX40/4-1BB costimulation by dramatically enhancing stem-like TIL presence via a CXCR3-dependent mechanism.ConclusionsOur findings provide new mechanistic insights into the interplay between components of combinatorial immunotherapy, where agonism of select costimulatory pathways seeds a pool of stem-like CD8+ T cells more responsive to immune checkpoint blockade (ICB).

scholarly journals The future of immunotherapy

2020 ◽  
Author(s):  
Cornelis J M Melief
Keyword(s):  
T Cells ◽  
T Cell ◽  
Ex Vivo ◽  
Tumor Infiltrating Lymphocytes ◽  
Checkpoint Control ◽  
Checks And Balances ◽  
Drug Conjugates ◽  
Cell Immunity ◽  
Anti Cd20 ◽  
Infiltrating Lymphocytes

Abstract During the last two decades two main schools of modern immunotherapy have come to the forefront. The chimeric anti-CD20 antibody rituximab that was introduced for the treatment of refractory follicular lymphoma in 1998 was one of the first examples of the school of passive immunotherapy. Subsequently major and ever more costly efforts were spent on the development of blockbuster monotherapies including other monoclonal but also bispecific antibodies of highly defined specificity and subclass, antibody-drug-conjugates (ADCs), as well as ex vivo expanded tumor infiltrating lymphocytes, CAR-transduced T cells, and TCR-transduced T cells. On the other hand there is the school that works towards active induction of patient B- or T-cell immunity against antigens of choice, or active tolerance against pathogenic allergens, auto-antigens or allo-antigens. Stradled in between these two approaches is treatment with blockers of T cell checkpoint control, which releases the brakes of T cells that have already responded to antigen. Extensive and detailed insight into the cellular and molecular interactions that regulate specific immune responses is indispensable in order to be able to optimize efficacy and rule out treatment related toxicity. This applies to all types of immunotherapy. Our knowledge of the checks and balances in the immune system is still increasing at an unprecedented pace, fostering ever more effective and specific (combination) immunotherapies and offering a rich harvest of innovative immunotherapies in the years ahead.

scholarly journals IMMU-02. NEOANTIGENS ARISING FROM ALTERNATIVE SPLICING EVENTS MAY BE TARGETED BY TUMOR INFILTRATING LYMPHOCYTES IN GLIOBLASTOMAS

2019 ◽  
Vol 21 (Supplement_6) ◽  
pp. vi118-vi119
Author(s):  
Alexander Lee ◽  
Yang Pan ◽  
Aaron Mochizuki ◽  
Mildred Galvez ◽  
Frances Chow ◽  
...  
Keyword(s):  
T Cells ◽  
Alternative Splicing ◽  
Single Cell ◽  
Rna Splicing ◽  
Ex Vivo ◽  
Tumor Infiltrating Lymphocytes ◽  
Sequencing Data ◽  
Synonymous Mutations ◽  
Alternative Splicing Events ◽  
Infiltrating Lymphocytes

Abstract INTRODUCTION Alternative splicing, the cellular process that converts premature mRNA to mature mRNA and allows for single genes to produce multiple protein products, is frequently dysregulated in many cancers, including glioblastoma. However, along with non-synonymous mutations in the DNA, altered splicing mechanisms in cancers may produce novel antigens (so-called neoantigens) that distinguish cancer cells from healthy cells and can thus be targeted by the immune system. METHODS We developed a new computation pipeline (IRIS – Isoform peptides from RNA splicing for Immunotherapy targets Screening) that took bulk RNA-sequencing data from 23 glioblastoma patient tumor samples and predicted neoantigens that may arise from alternative splicing events. We prioritized predicted neoantigens that arose in HLA*A02:01 and HLA*A03:01 patients and selected 8 potential neoantigens to generate peptide:MHC Class 1 dextramers. We tested PBMCs and/or ex vivo expanded tumor infiltrating lymphocytes (TIL) from 6 of our glioblastoma patients against these dextramers, sorted for any neoantigen-reactive T cells, and performed single-cell RNAsequencing on the sorted population to determine the TCR sequence. RESULTS Among the 8 predicted neoantigens tested, 7 of the neoantigens were recognized by at least 1 patient’s T cells. 1 HLA*A03:01 epitope was recognized in 3 of the 4 HLA*A03:01 patients tested and this epitope was highly positive in an expanded TIL population, representing 1.7% of all CD3+ CD8+ cells. When we sorted for those neoantigen reactive T cells from the expanded TIL population and performed single-cell RNAsequencing, we found 325 unique T cell clonotypes, but the top 10 clonotypes represented 83.6% of all TCR clonotypes. The most frequent TCR clonotype represented 39.1% of the repertoire and suggests that clonal expansion of a select few TCR clones occurred within the tumor. CONCLUSIONS In total, our data indicates that neoantigens arising from alternative splicing events may represent a potential target for immunotherapy in glioblastoma.

scholarly journals Characterization of neoantigen-specific T cells in cancer resistant to immune checkpoint therapies

2021 ◽  
Vol 118 (30) ◽  
pp. e2025570118
Author(s):  
Shamin Li ◽  
Yannick Simoni ◽  
Summer Zhuang ◽  
Austin Gabel ◽  
Shaokang Ma ◽  
...  
Keyword(s):  
T Cells ◽  
Immune Checkpoint ◽  
Tumor Regression ◽  
Tumor Model ◽  
Tumor Infiltrating Lymphocytes ◽  
Immune Checkpoint Blockade ◽  
T Cell Response ◽  
Histocompatibility Complex ◽  
Infiltrating Lymphocytes

Neoantigen-specific T cells are strongly implicated as being critical for effective immune checkpoint blockade treatment (ICB) (e.g., anti–PD-1 and anti–CTLA-4) and are being targeted for vaccination-based therapies. However, ICB treatments show uneven responses between patients, and neoantigen vaccination efficiency has yet to be established. Here, we characterize neoantigen-specific CD8+ T cells in a tumor that is resistant to ICB and neoantigen vaccination. Leveraging the use of mass cytometry combined with multiplex major histocompatibility complex (MHC) class I tetramer staining, we screened and identified tumor neoantigen–specific CD8+ T cells in the Lewis Lung carcinoma (LLC) tumor model (mRiok1). We observed an expansion of mRiok1-specific CD8+ tumor-infiltrating lymphocytes (TILs) after ICB targeting PD-1 or CTLA-4 with no sign of tumor regression. The expanded neoantigen-specific CD8+ TILs remained phenotypically and functionally exhausted but displayed cytotoxic characteristics. When combining both ICB treatments, mRiok1-specific CD8+ TILs showed a stem-like phenotype and a higher capacity to produce cytokines, but tumors did not show signs of regression. Furthermore, combining both ICB treatments with neoantigen vaccination did not induce tumor regression either despite neoantigen-specific CD8+ TIL expansion. Overall, this work provides a model for studying neoantigens in an immunotherapy nonresponder model. We showed that a robust neoantigen-specific T-cell response in the LLC tumor model could fail in tumor response to ICB, which will have important implications in designing future immunotherapeutic strategies.

Immune signatures associated with response to neoadjuvant PD-1 blockade in oral cavity cancer.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 6055-6055
Author(s):  
Hannah Knochelmann ◽  
Joshua Dean Horton ◽  
Megan Meek ◽  
Carsten Krieg ◽  
Cynthia Dawn Timmers ◽  
...  
Keyword(s):  
T Cells ◽  
Oral Cavity ◽  
Clinical Medicine ◽  
Ex Vivo ◽  
Tumor Infiltrating Lymphocytes ◽  
Effector Memory ◽  
Immune Profile ◽  
Phenotypic Differences ◽  
Small Cohort ◽  
Infiltrating Lymphocytes

6055 Background: PD-1 inhibition therapy has revolutionized clinical medicine as it can mediate durable responses in a small cohort of patients. Yet, it remains incompletely understood why these patients respond. To address this question, we studied patients with oral cavity squamous cell carcinoma (OCSCC) to elucidate immune phenotypes associated with response to nivolumab. Methods: We defined the immune profile from the blood and tumor of patients on neoadjuvant nivolumab. We tested if tumor-infiltrating lymphocytes (TIL) could be preferentially expanded ex vivo from nivolumab-responsive patients versus those who were either non-responsive or had never received nivolumab. During the course of therapy, we comprehensively profiled a number of surface markers on patients’ T cells to define their activation status, cytotoxic capacity and memory phenotype. Moreover, the immune profile of the peripheral blood was assessed pre- and post-nivolumab using high dimensional mass cytometry. Results: Regardless of PD-1 therapy, TIL were successfully expanded from 11 of the 12 patients. TIL were comprised of both CD4+ and CD8+ T cells. Additional investigation revealed that the frequency of CD4+ T cells and effector memory T cells in TIL correlated with disease progression (CD4: p = 0.04, r = 0.74, effector memory: p = 0.046, r = 0.74). TILs from responders expressed higher CD26 (p = 0.007, r = -0.88) and Tim3 (p = 0.045, r = -0.74) while PD-1, Lag3, and Ox40 were not differentially expressed based on response. Spearman correlation and Mann Whitney U test were used to assess phenotypic differences. Conclusions: We demonstrate, for the first time, that TIL can be reliably expanded from OCSCC patients on neoadjuvant nivolumab. Moreover, individuals who were responsive to PD-1 blockade had TIL expressing high levels of CD26 and Tim3. Future studies will explore if these markers are predictive of responses and if they contribute to treatment outcome.

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