scholarly journals Vaccines as Priming Tools for T Cell Therapy for Epithelial Cancers

Cancers ◽  
2021 ◽  
Vol 13 (22) ◽  
pp. 5819
Author(s):  
Lana E. Kandalaft ◽  
Alexandre Harari
Keyword(s):  
T Cells ◽  
T Cell ◽  
Checkpoint Inhibitors ◽  
Tumor Infiltrating Lymphocytes ◽  
T Cell Therapy ◽  
Epithelial Cancers ◽  
Cell Responses ◽  
Cancer Immunotherapies ◽  
Infiltrating Lymphocytes ◽  
Therapeutic Cancer Vaccines

Impressive progress has recently been made in the field of cancer immunotherapy with the adoptive transfer of T cells, a successful personalized strategy, and checkpoint inhibitors (CPI) having extended the survival of numerous patients. However, not all patients have been able to benefit from these innovations. A key determinant of the responsiveness to cancer immunotherapies is the presence of T cells within the tumors. These tumor-infiltrating lymphocytes (TILs) are crucial in controlling tumor growth and their activity is being potentiated by immunotherapies. Although some epithelial cancers are associated with spontaneous T-cell and B-cell responses, which makes them good candidates for immunotherapies, it remains to create strategies that would promote lymphocyte infiltration and enable sustained immune responses in immune-resistant tumors. Therapeutic cancer vaccines hold the potential of being able to render “cold”, poorly infiltrated tumors into “hot” tumors that would be receptive to cellular immunotherapies. In this review, we elaborate on the obstacles that need to be overcome and the strategies that are being explored to that end, including various types of antigen repertoires and different vaccine platforms and combinations with other available treatments.

scholarly journals Qualitative Analysis of Tumor-Infiltrating Lymphocytes across Human Tumor Types Reveals a Higher Proportion of Bystander CD8+ T Cells in Non-Melanoma Cancers Compared to Melanoma

Cancers ◽  
2020 ◽  
Vol 12 (11) ◽  
pp. 3344
Author(s):  
Aishwarya Gokuldass ◽  
Arianna Draghi ◽  
Krisztian Papp ◽  
Troels Holz Borch ◽  
Morten Nielsen ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
T Cells ◽  
T Cell ◽  
Tumor Infiltrating Lymphocytes ◽  
Autologous Tumor ◽  
Epithelial Cancers ◽  
Single Cell Rna Sequencing ◽  
Tumor Types ◽  
Infiltrating Lymphocytes

Background: Human intratumoral T cell infiltrates can be defined by quantitative or qualitative features, such as their ability to recognize autologous tumor antigens. In this study, we reproduced the tumor-T cell interactions of individual patients to determine and compared the qualitative characteristics of intratumoral T cell infiltrates across multiple tumor types. Methods: We employed 187 pairs of unselected tumor-infiltrating lymphocytes (TILs) and autologous tumor cells from patients with melanoma, renal-, ovarian-cancer or sarcoma, and single-cell RNA sequencing data from a pooled cohort of 93 patients with melanoma or epithelial cancers. Measures of TIL quality including the proportion of tumor-reactive CD8+ and CD4+ TILs, and TIL response polyfunctionality were determined. Results: Tumor-specific CD8+ and CD4+ TIL responses were detected in over half of the patients in vitro, and greater CD8+ TIL responses were observed in melanoma, regardless of previous anti-PD-1 treatment, compared to renal cancer, ovarian cancer and sarcoma. The proportion of tumor-reactive CD4+ TILs was on average lower and the differences less pronounced across tumor types. Overall, the proportion of tumor-reactive TILs in vitro was remarkably low, implying a high fraction of TILs to be bystanders, and highly variable within the same tumor type. In situ analyses, based on eight single-cell RNA-sequencing datasets encompassing melanoma and five epithelial cancers types, corroborated the results obtained in vitro. Strikingly, no strong correlation between the proportion of CD8+ and CD4+ tumor-reactive TILs was detected, suggesting the accumulation of these responses in the tumor microenvironment to follow non-overlapping biological pathways. Additionally, no strong correlation between TIL responses and tumor mutational burden (TMB) in melanoma was observed, indicating that TMB was not a major driving force of response. No substantial differences in polyfunctionality across tumor types were observed. Conclusions: These analyses shed light on the functional features defining the quality of TIL infiltrates in cancer. A significant proportion of TILs across tumor types, especially non-melanoma, are bystander T cells. These results highlight the need to develop strategies focused on the tumor-reactive TIL subpopulation.

Expression of LAG-3 by tumor-infiltrating lymphocytes is coincident with the suppression of latent membrane antigen–specific CD8+ T-cell function in Hodgkin lymphoma patients

Blood ◽  
2006 ◽  
Vol 108 (7) ◽  
pp. 2280-2289 ◽  
Author(s):  
Maher K. Gandhi ◽  
Eleanore Lambley ◽  
Jaikumar Duraiswamy ◽  
Ujjwal Dua ◽  
Corey Smith ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Regulatory T Cells ◽  
Hodgkin Lymphoma ◽  
Cell Function ◽  
T Cell Responses ◽  
Tumor Infiltrating Lymphocytes ◽  
Cd8 T Cell ◽  
Cell Responses ◽  
Infiltrating Lymphocytes

AbstractIn Hodgkin lymphoma (HL), the malignant Hodgkin Reed-Sternberg (HRS) cells constitute only 0.5% of 10% of the diseased tissue. The surrounding cellular infiltrate is enriched with T cells that are hypothesized to modulate antitumor immunity. We show that a marker of regulatory T cells, LAG-3, is strongly expressed on infiltrating lymphocytes present in proximity to HRS cells. Circulating regulatory T cells (CD4+ CD25hi CD45 ROhi, CD4+ CTLA4hi, and CD4+ LAG-3hi) were elevated in HL patients with active disease when compared with remission. Longitudinal profiling of EBV-specific CD8+ T-cell responses in 94 HL patients revealed a selective loss of interferon-γ expression by CD8+ T cells specific for latent membrane proteins 1 and 2 (LMP1/2), irrespective of EBV tissue status. Intratumoral LAG-3 expression was associated with EBV tissue positivity, whereas FOXP3 was linked with neither LAG-3 nor EBV tissue status. The level of LAG-3 and FOXP3 expression on the tumor-infiltrating lymphocytes was coincident with impairment of LMP1/2-specific T-cell function. In vitro pre-exposure of peripheral blood mononuclear cells to HRS cell line supernatant significantly increased the expansion of regulatory T cells and suppressed LMP-specific T-cell responses. Deletion of CD4+ LAG-3+ T cells enhanced LMP-specific reactivity. These findings indicate a pivotal role for regulatory T cells and LAG-3 in the suppression of EBV-specific cell-mediated immunity in HL.

Immunogenicity and tolerability of personalized mRNA vaccine mRNA-4650 encoding defined neoantigens expressed by the autologous cancer.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 2643-2643 ◽  
Author(s):  
Gal Cafri ◽  
Jared J. Gartner ◽  
Kristen Hopson ◽  
Robert S. Meehan ◽  
Tal Z. Zaks ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Checkpoint Inhibitors ◽  
Objective Response ◽  
Adoptive T Cell Therapy ◽  
High Avidity ◽  
T Cell Epitopes ◽  
Cell Reactivity ◽  
T Cell Therapy ◽  
Epithelial Cancers

2643 Background: Therapeutic vaccination against cancer has proven very challenging with little clinical benefit. Vaccines against non-viral tumors have mainly targeted differentiation antigens, cancer testis antigens, and over-expressed antigens. However, negative selection in the thymus against these normal non-mutated antigens severely limits the ability to generate high avidity anti-cancer T-cells. The importance of neoantigens to each patient’s unique cancer as targets for immunotherapy has been extensively studied, by our group and others. It is now clear that neoantigen-specific T-cells are present in most cancers and these neoantigens derived from somatic mutations offer a specific and highly immunogenic target for personalized vaccination. We developed a process to identify immunogenic T-cell epitopes derived from tumor-specific mutations using tumor-infiltrating lymphocytes. Methods: We combined, for the first time, validated defined neoantigens, predicted neoepitopes and mutations in driver genes into a single mRNA concatemer (mRNA-4650) to vaccinate patients with metastatic common epithelial cancers. We are conducting a phase I/II trial in patients with metastatic melanoma, gastrointestinal, or genitourinary cancers with at least one lesion that is resectable. Patients must have an ECOG status of ≤1 with adequate organ and bone marrow function. Patients are vaccinated intramuscularly at two-week intervals for four cycles, and dosing may be repeated for a second course of vaccination. Key primary endpoints are safety, tolerability and the development of T-cell reactivity as well as objective response rate. Results: mRNA-4650 is safe at all dose levels studied to date with no reported DLTs or drug related SAEs. Neoantigen specific CD8 and CD4 T cells responses against neoepitopes included in the vaccine have been observed and no tumor regressions were seen. Conclusions: Our data show that such a personalized mRNA vaccination is feasible and can elicit neoantigen specific T cell responses. Combination of vaccines with checkpoint inhibitors or adoptive T cell therapy can open the possibility to develop effective immunotherapies for patients with the common epithelial cancers. Clinical trial information: NCT03480152.

773 Adoptive Cell Therapy Response in Melanoma is Mediated by Stem-like CD8 T cells

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A822-A822
Author(s):  
Sri Krishna ◽  
Frank Lowery ◽  
Amy Copeland ◽  
Stephanie Goff ◽  
Grégoire Altan-Bonnet ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Therapy ◽  
Single Cell ◽  
Cd8 T Cells ◽  
Tumor Infiltrating Lymphocytes ◽  
High Dimensional ◽  
Tumor Control ◽  
Intrinsic Factors ◽  
Infiltrating Lymphocytes

BackgroundAdoptive T cell therapy (ACT) utilizing ex vivo-expanded autologous tumor infiltrating lymphocytes (TILs) can result in complete regression of human cancers.1 Successful immunotherapy is influenced by several tumor-intrinsic factors.2 3 Recently, T cell-intrinsic factors have been associated with immunotherapy response in murine and human studies.4 5 Analyses of tumor-reactive TILs have concluded that anti-tumor neoantigen-specific TILs are enriched in subsets defined by the expression of PD-1 or CD39.6 7 Thus, there is a lack of consensus regarding the tumor-reactive TIL subset that is directly responsible for successful immunotherapies such as ICB and ACT. In this study, we attempted to define the fitness landscape of TIL-enriched infusion products to specifically understand its phenotypic impact on human immunotherapy responses.MethodsWe compared the phenotypic differences that could distinguish bulk ACT infusion products (I.P.) administered to patients who had complete response to therapy (complete responders, CRs, N = 24) from those whose disease progressed following ACT (non-responders, NRs, N = 30) by high dimensional single cell protein and RNA analysis of the I.P. We further analyzed the phenotypic states of anti-tumor neoantigen specific TILs from patient I.P (N = 26) by flow cytometry and single cell transcriptomics.ResultsWe identified two CD8+ TIL populations associated with clinical outcomes: a memory-progenitor CD39-negative stem-like TIL (CD39-CD69-) in the I.P. associated with complete cancer regression (overall survival, P < 0.0001, HR = 0.217, 95% CI 0.101 to 0.463) and TIL persistence, and a terminally differentiated CD39-positive TIL (CD39+CD69+) population associated with poor TIL persistence post-treatment. Although the majority (>65%) of neoantigen-reactive TILs in both responders and non-responders to ACT were found in the differentiated CD39+ state, CR infusion products also contained a pool of CD39- stem-like neoantigen-specific TILs (median = 8.8%) that was lacking in NR infusion products (median = 23.6%, P = 1.86 x 10-5). Tumor-reactive stem-like T cells were capable of self-renewal, expansion, and persistence, and mediated superior anti-tumor response in vivo.ConclusionsOur results support the hypothesis that responders to ACT received infusion products containing a pool of stem-like neoantigen-specific TILs that are able to undergo prolific expansion, give rise to differentiated subsets, and mediate long-term tumor control and T cell persistence, in line with recent murine ICB studies mediated by TCF+ progenitor T cells.4 5 Our data also suggest that TIL subsets mediating ACT-response (stem-like CD39-) might be distinct from TIL subsets enriched for anti-tumor-reactivity (terminally differentiated CD39+) in human TIL.6 7AcknowledgementsWe thank Don White for curating the melanoma patient cohort, and J. Panopoulos (Flowjo) for helpful discussions on high-dimensional analysis, and NCI Surgery Branch members for helpful insights and suggestions. S. Krishna acknowledges funding support from NCI Director’s Innovation Award from the National Cancer Institute.Trial RegistrationNAEthics ApprovalThe study was approved by NCI’s IRB ethics board.ReferencesGoff SL, et al. Randomized, prospective evaluation comparing intensity of lymphodepletion before adoptive transfer of tumor-infiltrating lymphocytes for patients with metastatic melanoma. J Clin Oncol 2016;34:2389–2397.Snyder A, et al. Genetic basis for clinical response to CTLA-4 blockade in melanoma. N Engl J Med 2014;371:2189–2199.McGranahan N, et al. Clonal neoantigens elicit T cell immunoreactivity and sensitivity to immune checkpoint blockade. Science 2016;351:1463–1469.Sade-Feldman M, et al. Defining T cell states associated with response to checkpoint immunotherapy in melanoma. Cell 2019;176:404.Miller BC, et al. Subsets of exhausted CD8 T cells differentially mediate tumor control and respond to checkpoint blockade. Nat. Immunol 2019;20:326–336.Simoni Y, et al. Bystander CD8 T cells are abundant and phenotypically distinct in human tumour infiltrates. Nature 2018;557:575–579.Gros A, et al. PD-1 identifies the patient-specific CD8+ tumor-reactive repertoire infiltrating human tumors. J Clin Invest 2014;124:2246–2259.

scholarly journals Engineering adoptive T cell therapy to co-opt Fas ligand-mediated death signaling in ovarian cancer enhances therapeutic efficacy

2021 ◽  
Author(s):  
Kristin G. Anderson ◽  
Shannon K. Oda ◽  
Breanna M. Bates ◽  
Madison G. Burnett ◽  
Magdalia Rodgers Suarez ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
T Cells ◽  
Cell Death ◽  
T Cell ◽  
Cell Therapy ◽  
Tumor Vasculature ◽  
Adoptive T Cell Therapy ◽  
T Cell Therapy ◽  
Tumor Bearing ◽  
Infiltrating Lymphocytes

Background: In the U.S., more than 50% of ovarian cancer patients die within 5 years of diagnosis, highlighting the need for innovations such as engineered T cell therapies. Mesothelin (Msln) is an attractive immunotherapy target for this cancer, as it is overexpressed by the tumor and contributes to malignant and invasive phenotypes, making antigen loss disadvantageous to the tumor. We previously showed that adoptively transferred T cells engineered to be Msln-specific (TCR1045) preferentially accumulate within established ovarian tumors, delay tumor growth and significantly prolong survival in the ID8VEGF mouse model. However, T cell persistence and anti-tumor activity were not sustained, and we and others have previously detected FasL in the tumor vasculature and the tumor microenvironment (TME) of human and murine ovarian cancers, which can induce apoptosis in infiltrating lymphocytes expressing Fas receptor (Fas). Methods: To concurrently overcome this mechanism for potential immune evasion and enhance T cell responses, we generated an immunomodulatory fusion protein (IFP) containing the Fas extracellular binding domain fused to a 4-1BB co-stimulatory domain, rather than the natural death domain. T cells engineered to express TCR1045 alone or in combination with the IFP were transferred into ID8VEGF-tumor bearing mice and evaluated for persistence, proliferation, anti-tumor cytokine production, and therapeutic efficacy. Results: Relative to T cells modified only to express TCR1045, T cells engineered to express both TCR1045 and a Fas IFP preferentially persisted in the TME of tumor-bearing mice due to improved T cell proliferation and survival. Moreover, adoptive immunotherapy with IFP+ T cells significantly prolonged survival in tumor-bearing mice, relative to TCR1045 T cells lacking the IFP. Conclusions: Fas/FasL signaling can mediate T cell death in the ovarian cancer microenvironment, as well as induce activation-induced cell death, an apoptotic mechanism responsible for regulating T cell expansion. Upregulation of FasL by tumor cells and tumor vasculature represents a mechanism for protecting growing tumors from attack by tumor-infiltrating lymphocytes. As many solid tumors overexpress FasL, an IFP that converts the Fas-mediated death signal into pro-survival and proliferative signals may provide an opportunity to enhance engineered adoptive T cell therapy against many malignancies.

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.

Modeling and simulation of the “IL-36 cytokine” and CAR-T cells interplay in cancer onset

2021 ◽  
Author(s):  
Khaled A. Al-Utaibi ◽  
Alessandro Nutini ◽  
Ayesha Sohail ◽  
Robia Arif ◽  
Sümeyye Tunc ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Adoptive Immunotherapy ◽  
Checkpoint Inhibitors ◽  
Antitumor Action ◽  
Adoptive Therapy ◽  
T Cell Therapy ◽  
Car T Cells ◽  
Car T Cell ◽  
Car T

Background: CAR-T cells are chimeric antigen receptor (CAR)-T cells; they are target-specific engineered cells on tumor cells and produce T cell-mediated antitumor responses. CAR-T cell therapy is the “first-line” therapy in immunotherapy for the treatment of highly clonal neoplasms such as lymphoma and leukemia. This adoptive therapy is currently being studied and tested even in the case of solid tumors such as osteosarcoma since, precisely for this type of tumor, the use of immune checkpoint inhibitors remained disappointing. Although CAR-T is a promising therapeutic technique, there are therapeutic limits linked to the persistence of these cells and to the tumor’s immune escape. CAR-T cell engineering techniques are allowed to express interleukin IL-36, and seem to be much more efficient in antitumoral action. IL-36 is involved in the long-term antitumor action, allowing CAR-T cells to be more efficient in their antitumor action due to a “cross-talk” action between the “IL-36/dendritic cells” axis and the adaptive immunity. Methods: This analysis makes the model useful for evaluating cell dynamics in the case of tumor relapses or specific understanding of the action of CAR-T cells in certain types of tumor. The model proposed here seeks to quantify the action and interaction between the three fundamental elements of this antitumor activity induced by this type of adoptive immunotherapy: IL-36, “armored” CAR-T cells (i.e., engineered to produce IL-36) and the tumor cell population, focusing exclusively on the action of this interleukin and on the antitumor consequences of the so modified CAR-T cells. Mathematical model was developed and numerical simulations were carried out during this research. The development of the model with stability analysis by conditions of Routh–Hurwitz shows how IL-36 makes CAR-T cells more efficient and persistent over time and more effective in the antitumoral treatment, making therapy more effective against the “solid tumor”. Findings: Primary malignant bone tumors are quite rare (about 3% of all tumors) and the vast majority consist of osteosarcomas and Ewing’s sarcoma and, approximately, the 20% of patients undergo metastasis situations that is the most likely cause of death. Interpretation: In bone tumor like osteosarcoma, there is a variation of the cellular mechanical characteristics that can influence the efficacy of chemotherapy and increase the metastatic capacity; an approach related to adoptive immunotherapy with CAR-T cells may be a possible solution because this type of therapy is not influenced by the biomechanics of cancer cells which show peculiar characteristics.

scholarly journals Cold-Inducible RNA Binding Protein as a Vaccination Platform to Enhance Immunotherapeutic Responses against Hepatocellular Carcinoma

Cancers ◽  
2020 ◽  
Vol 12 (11) ◽  
pp. 3397
Author(s):  
Leyre Silva ◽  
Josune Egea ◽  
Lorea Villanueva ◽  
Marta Ruiz ◽  
Diana Llopiz ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
T Cell ◽  
Rna Binding ◽  
Checkpoint Inhibitors ◽  
Binding Protein ◽  
Rna Binding Protein ◽  
T Cell Responses ◽  
Tumor Infiltrating Lymphocytes ◽  
Cell Responses ◽  
Tlr4 Ligand

Therapies based on immune checkpoint inhibitors (ICPI) have yielded promising albeit limited results in patients with hepatocellular carcinoma (HCC). Vaccines have been proposed as combination partners to enhance response rates to ICPI. Thus, we analyzed the combined effect of a vaccine based on the TLR4 ligand cold-inducible RNA binding protein (CIRP) plus ICPI. Mice were immunized with vaccines containing ovalbumin linked to CIRP (OVA-CIRP), with or without ICPI, and antigen-specific responses and therapeutic efficacy were tested in subcutaneous and orthotopic mouse models of liver cancer. OVA-CIRP elicited polyepitopic T-cell responses, which were further enhanced when combined with ICPI (anti-PD-1 and anti-CTLA-4). Combination of OVA-CIRP with ICPI enhanced ICPI-induced therapeutic responses when tested in subcutaneous and intrahepatic B16-OVA tumors, as well as in the orthotopic PM299L HCC model. This effect was associated with higher OVA-specific T-cell responses in the periphery, although many tumor-infiltrating lymphocytes still displayed an exhausted phenotype. Finally, a new vaccine containing human glypican-3 linked to CIRP (GPC3-CIRP) induced clear responses in humanized HLA-A2.01 transgenic mice, which increased upon combination with ICPI. Therefore, CIRP-based vaccines may generate anti-tumor immunity to enhance ICPI efficacy in HCC, although blockade of additional checkpoint molecules and immunosuppressive targets should be also considered.

Th-17 Lymphocytes, Not Regulatory T Cells, Mediate Immune Regulation of Bone Marrow Infiltrating Lymphocytes and Induce Osteoclast Activation in Multiple Myeloma.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 811-811 ◽  
Author(s):  
Kimberly A. Noonan ◽  
Judy Anderson ◽  
Stephanie Mgebroff ◽  
Paolo Serafini ◽  
David Roodman ◽  
...  
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
T Cell ◽  
Bone Disease ◽  
Osteoclast Differentiation ◽  
Adoptive T Cell Therapy ◽  
T Cell Therapy ◽  
Th 17 ◽  
Tumor Specificity ◽  
Infiltrating Lymphocytes

Abstract The bone marrow of myeloma patients is a reservoir of marrow infiltrating lymphocytes (MILs) that upon activation with anti-CD3 and anti-CD28 antibodies show significant tumor specificity against both mature myeloma plasma cells and their clonotypic precursors, whereas activated peripheral blood lymphocytes (PBLs) fail to demonstrate any tumor specificity. Here we examine the major differences between MILs and PBLs of both myeloma patients and normal donors. In myeloma, CD4+/CD25+ MILs lack a regulatory T-cell (Treg) phenotype as shown by the absence of FoxP3 expression and the inability to suppress tumor-specific proliferation of effector T cells. In contrast, the CD4+/CD25+ PBLs express FoxP3 and suppress tumor specific proliferation. Analysis of MILs and PBLs from normal individuals reveals the exact opposite (more Tregs in the marrow than blood). Considering the abundance of plasma cell-derived IL-6 in myeloma marrow, we hypothesize that IL-6 skewing of MILs towards the effector Th17 phenotype could explain the reciprocal paucity of Tregs in myeloma and relative abundance in normal bone marrows. Intracellular staining shows increased expression of IL-17 in myeloma CD4 MILs (2.7%) as compared to either myeloma PBLs (0.02%) or normal MILs (0.7%). The Th17 cytokine secretion pattern also appears more pronounced in myeloma-derived MILs as compared to either myeloma PBLs or normal MILs respectively (see table). Th17 T cells have recently been implicated in osteoclastogenesis of rheumatoid arthritis. In fact, bone marrow serum IL-17 levels correlate with the degree of lytic bone disease. In experiments utilizing M-CSF and RANK-L as the osteoclast differentiation medium, we show that the addition of IL-17 to the culture medium increases the number of mature osteoclasts by 2.3 fold whereas γIFN reduces mature osteoclast numbers by 80%. These findings explain the profound differences seen in MILs of normal and myeloma patients and implicate Th17 MILs in the generation of lytic bone disease. Activation of myeloma MILs with anti-CD3/CD28 skews the population from Th17 to a γIFN-producing Th1 phenotype. As such, targeting Th17 T cells or utilizing adoptive T cell therapy with activated, γIFN-producing MILs may represent a novel therapeutic mechanism to target osteoclastogenesis and reduce bone disease in myeloma. Th-17 Cytokine Profile N=56 MM MILs MM PBLs NL MILs IL-6 (pg/ml) 30 3.7 6.5 IL-23 (pg/ml) 246 19.6 35.9 IL-17 (pg/ml) 12.2 0.4 5.1

scholarly journals The mutational load and a T-cell inflamed tumor phenotype identify ovarian cancer patients rendering tumor-reactive T cells from PD-1+ tumor-infiltrating lymphocytes

2020 ◽  
Author(s):  
Diego Salas-Benito ◽  
Enrique Conde ◽  
Ibon Tamayo-Uria ◽  
Uxua Mancheño ◽  
Edurne Elizalde ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
T Cells ◽  
T Cell ◽  
Predictive Biomarkers ◽  
Tumor Infiltrating Lymphocytes ◽  
Ovarian Tumors ◽  
Autologous Tumor ◽  
Tumor Mutational Burden ◽  
Nanostring Technology ◽  
Infiltrating Lymphocytes

Abstract Background: Adoptive immunotherapy with tumor-infiltrating lymphocytes (TIL) may benefit from the use of selective markers, such as programmed cell death protein 1 (PD-1), for tumor-specific T-cell enrichment, as well as predictive biomarkers that help identify those patients capable of rendering tumor-reactive TIL products. We have investigated this in ovarian cancer (OC) patients as candidate for TIL therapy implementation. Methods: PD-1- and PD-1+ CD8 TILs were isolated from resected ovarian tumors and, after polyclonal expansion, TIL products were tested against autologous tumor cells. Reactivity was assessed by IFNg production (ELISPOT) and upregulation of CD137. Baseline tumor samples were examined using flow cytometry, multiplexed quantitative immunofluorescence, Nanostring technology, for gene expression profile (GEP) analyses, as well as a next generation sequencing gene panel, for tumor mutational burden (TMB) calculation, to identify those features that distinguished patients with tumor-reactive and non-tumor-reactive TIL products.Results: Tumor-reactive TILs were detected in half of patients and were exclusively present in cells derived from the PD-1+ fraction. Flow-cytometric studies revealed that fresh tumors from patients rendering tumor-reactive TILs presented a significantly higher frequency of CD137+ cells within the PD1+CD8+ subset. Multiplexed immunofluorescence supported this finding, which was particularly striking in intraepithelial CD8 TILs. Baseline GEP analysis showed that patients rendering tumor-reactive TILs exhibited a significantly higher T-cell inflamed signature. Despite no correlation between TMB and GEP, both parameters stratified tumors, with patients with higher TMB and/or T-cell inflamed signature score rendering tumor-reactive TILs. Conclusion: We have demonstrated that PD-1 identifies autologous-tumor specific CD8 T cells infiltrating ovarian tumors and have uncovered predictive factors that identify OC patients who are likely to render tumor-reactive cells from PD-1+ TILs. These findings have important implications for improving the efficacy of TIL therapy in OC.

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