508 Different neoantigen expression patterns impact the strength of anti-tumor immune responses

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A544-A544
Author(s):  
Kim Nguyen ◽  
Stefani Spranger ◽  
Christopher Copeland
Keyword(s):  
Immune Response ◽  
T Cells ◽  
Tumor Cells ◽  
Tumor Immunity ◽  
Cd8 T Cells ◽  
Expression Patterns ◽  
Tumor Model ◽  
Immune Checkpoint Blockade ◽  
List Type ◽  
Patient Response

BackgroundMany cancer immunotherapies depend on the ability of cytotoxic CD8+ T cells to recognize neoantigens on MHCI complexes to effectively eliminate tumor cells. However, patient response following immunotherapy is highly variable, with recent work suggesting that neoantigen expression patterns can impair patient response. Specifically, it was observed that the immune response is dampened when neoantigens are expressed only by a subset of tumor cells (heterogeneous expression).1 To study why anti-tumor immunity is reduced in a heterogeneous setting we developed a transplant murine tumor model engineered to express neoantigens in a heterogeneous pattern or homogenously.MethodsA curated list of neoantigens with varying predicted MCHI binding affinities was used to established an array of cell lines expressing at one to three neoantigens. The lines were inoculated subcutaneously in immunocompetent mice as mixtures (heterogenous) or as a single line (homogenous) to study the resulting immune response. Tumors were harvested at days 7, 10 and 14 and flow cytometry analysis was used to phenotype infiltrating immune populations, including antigen-specific CD8+ T cells. ELISpot assays were performed using splenocytes from the same timepoints to determine the frequency of antigen-specific T cells in the periphery.ResultsCompared to neoantigens predicted to bind weakly to MHCI, neoantigens predicted to bind strongly elicited robust expansion of antigen-specific T cells in the periphery and tumors expressing these antigens alone exhibited greater numbers of tumor infiltrating T cells. Homogenous expression of two neoantigens was found to enhance anti-tumor immunity by increasing the frequency of tumor-reactive T cells. Further, homogenous expression of two neoantigens induced protective immunity against antigens, including those that failed to be controlled when expressed alone.ConclusionsUsing our novel reductionist tumor model, our results suggest that a more robust response against weak antigens could be induced if a response against a strong, highly immunogenic neoantigen is mounted simultaneously. This observation has direct implications for the design of neoantigen vaccines either as mono- or combination immunotherapies, especially in the setting of a heterogeneous neoantigen expression pattern.ReferencesMcGranahan N, Furness AJ, Rosenthal R, Ramskov S, Lyngaa R, Saini SK, Jamal-Hanjani M, Wilson GA, Birkbak NJ, Hiley CT, Watkins TB, Shafi S, Murugaesu N, Mitter R, Akarca AU, Linares J, Marafioti T, Henry JY, Van Allen EM, Miao D, Schilling B, Schadendorf D, Garraway LA, Makarov V, Rizvi NA, Snyder A, Hellmann MD, Merghoub T, Wolchok JD, Shukla SA, Wu CJ, Peggs KS, Chan TA, Hadrup SR, Quezada SA, Swanton C. Clonal neoantigens elicit T cell immunoreactivity and sensitivity to immune checkpoint blockade. Science 2016 Mar 25;351(6280):1463–9.

IMMU-44. AN IMMUNOTHERAPEUTIC VACCINE COMPOSED OF IRRADIATED WHOLE TUMOR CELLS PULSED WITH MANNAN-BAM, TLR LIGANDS AND ANTI-CD40 ANTIBODY INDUCES POTENT IMMUNE RESPONSE IN PRECLINICAL GBM ANIMAL MODEL

2021 ◽  
Vol 23 (Supplement_6) ◽  
pp. vi102-vi102
Author(s):  
Herui Wang ◽  
Rogelio Medina ◽  
Juan Ye ◽  
Pashayar Lookian ◽  
Ondrej Uher ◽  
...  
Keyword(s):  
Immune Response ◽  
T Cells ◽  
Tumor Cells ◽  
T Lymphocyte ◽  
Cd8 T Cells ◽  
Therapeutic Efficacy ◽  
Poly I:C ◽  
Control Group ◽  
Complete Regression ◽  
Adaptive Immune

Abstract Despite numerous therapeutic advances, the treatment of glioblastoma multiforme (GBM) remains a challenge, with current 5-year survival rates estimated at 4%. Multiple characteristic elements of GBM contribute to its treatment-resistance, including its low immunogenicity and its highly immunosuppressive microenvironment that can effectively disarm adaptive immune responses. Hence, therapeutic strategies that aim to boost T-lymphocyte mediated responses against GBM are of great therapeutic value. Herein, we present a therapeutic vaccination strategy that promotes the phagocytosis of tumor cells, enhances tumor antigen presentation, and induces a tumor-specific adaptive immune response. This strategy consists of vaccinations with irradiated whole tumor cells (rWTC) pulsed with phagocytic agonists (Mannan-BAM), TLR ligands [LTA, Poly (I:C), and R-848], and anti-CD40 antibody (collectively abbreviated as rWTC-MBTA). We evaluated the therapeutic efficacy of rWTC-MBTA strategy in a mouse syngeneic GL261 orthotopic GBM tumor model. rWTC-MBTA or vehicle control were administered subcutaneously over the right foreleg three days after intracranial injection of GL261 cells. Complete regression (CR) of intracranial tumors was achieved in 70% (7/10) of rWTC-MBTA treated animals while none survived in the control group. Immunophenotyping analyses of peripheral lymph nodes and brain tumors of rWTC-MBTA treated mice demonstrated: (1) increased mature dendritic cells and MHC II+ monocytes; (2) increased effector (CD62L-CD44+) CD4-T and CD8-T cells; (3) increased cytotoxic IFNγ-, TNFα-, and granzyme B-secreting CD4-T and CD8-T cells. Of note, the therapeutic efficacy of rWTC-MBTA disappeared in CD4-T and/or CD8-T lymphocyte depleted mice. Three mice that achieved CR were rechallenged with 50k GL261 cells intracranially 14 months after the last rWTC-MBTA treatment and all rechallenged animals resisted GL261 tumor development, confirming the establishment of long-term immunological memory against GL261 tumor cells. Collectively, our study demonstrated that rWTC-MBTA strategy can effectively activate antigen presenting cells and induce more favorable T-cell signatures in the GBM tumors.

scholarly journals Early Response of CD8+ T Cells in COVID-19 Patients

2021 ◽  
Vol 11 (12) ◽  
pp. 1291
Author(s):  
Deni Ramljak ◽  
Martina Vukoja ◽  
Marina Curlin ◽  
Katarina Vukojevic ◽  
Maja Barbaric ◽  
...  
Keyword(s):  
Gene Expression ◽  
Immune Response ◽  
T Cells ◽  
Mrna Expression ◽  
Cd8 T Cells ◽  
Expression Profiles ◽  
Expression Patterns ◽  
Effector Memory ◽  
Healthy Controls ◽  
Ifn Γ

Healthy and controlled immune response in COVID-19 is crucial for mild forms of the disease. Although CD8+ T cells play important role in this response, there is still a lack of studies showing the gene expression profiles in those cells at the beginning of the disease as potential predictors of more severe forms after the first week. We investigated a proportion of different subpopulations of CD8+ T cells and their gene expression patterns for cytotoxic proteins (perforin-1 (PRF1), granulysin (GNLY), granzyme B (GZMB), granzyme A (GZMA), granzyme K (GZMK)), cytokine interferon-γ (IFN-γ), and apoptotic protein Fas ligand (FASL) in CD8+ T cells from peripheral blood in first weeks of SARS-CoV-2 infection. Sixteen COVID-19 patients and nine healthy controls were included. The absolute counts of total lymphocytes (p = 0.007), CD3+ (p = 0.05), and CD8+ T cells (p = 0.01) in COVID-19 patients were significantly decreased compared to healthy controls. In COVID-19 patients in CD8+ T cell compartment, we observed lower frequency effector memory 1 (EM1) (p = 0.06) and effector memory 4 (EM4) (p < 0.001) CD8+ T cells. Higher mRNA expression of PRF1 (p = 0.05) and lower mRNA expression of FASL (p = 0.05) at the fifth day of the disease were found in COVID-19 patients compared to healthy controls. mRNA expression of PRF1 (p < 0.001) and IFN-γ (p < 0.001) was significantly downregulated in the first week of disease in COVID-19 patients who progressed to moderate and severe forms after the first week, compared to patients with mild symptoms during the entire disease course. GZMK (p < 0.01) and FASL (p < 0.01) mRNA expression was downregulated in all COVID-19 patients compared to healthy controls. Our results can lead to a better understanding of the inappropriate immune response of CD8+ T cells in SARS-CoV2 with the faster progression of the disease.

Generation of CD8 T Cell-Mediated Protective Immunity against Tumor Escapees

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 2623-2623 ◽  
Author(s):  
Bindu Varghese ◽  
Behnaz Taidi ◽  
Adam Widman ◽  
James Do ◽  
R. Levy
Keyword(s):  
Immune Response ◽  
T Cells ◽  
T Cell ◽  
Tumor Growth ◽  
Tumor Cells ◽  
Cd8 T Cells ◽  
Cell Lymphoma ◽  
Ex Vivo ◽  
B Cell Lymphoma ◽  
Cd8 T Cell

Abstract Introduction: Anti-idiotype antibodies against B cell lymphoma have shown remarkable success in causing tumor regression in the clinic. In addition to their known ability to mediate ADCC, anti-idiotype antibodies have also been shown to directly inhibit the proliferation of tumor cells by sending negative growth signals via the target idiotype. However, further studies to investigate this mechanism have been hindered by the failure of patient tumor cells to grow ex vivo. Methods and Results: In order to study this phenomenon further, we developed an antibody against the idiotype on an A20 mouse B lymphoma cell line. A radioactive thymidine incorporation assay showed decreased A20 cell proliferation in the presence of the anti-id antibody ex vivo. In vivo, when mice were treated intraperitoneally (i.p.) with 100 μg of antibody 3 hours post-tumor inoculation (1×106 A20 subcutaneously (s.c.)), tumor growth was delayed for greater than 40 days after which the tumor began to grow once again. Further analysis of these escaping tumor cells by flow cytometry showed that that the tumor cells escaped the antibody-mediated immune response by down-regulating expression of idiotype and IgG on their surfaces although the cells retained idiotype expression intracellularly. This down-regulation of surface idiotype rendered the tumor cells resistant to both ADCC and signaling-induced cell death. The addition of an immunostimulatory bacterial mimic (CpG-DNA; 100 μg × 5 intratumoral (i.t.) injections; Days 2, 3 4, 6 & 8) to antibody therapy (Day 0; 100 μg i.p.) cured large established tumors (Day 0 = 1 cm2) and prevented the occurrence of tumor escapees (p&lt;0.0001). Antibody plus CpG combination therapy in tumor-bearing mice deficient for CD8+ T cells demonstrated the critical role of CD8+ T cells in A20 tumor eradication (p&lt;0.005). Depletion of CD4+ T cells was found to have no significant impact on the therapy. We also found that when mice were inoculated with two tumors and treated with anti-idiotype antibody (i.p.) followed by intratumoral CpG in just one tumor (Day 0=1 cm2; anti-idiotype antibody 100 μg Day 0; 100 μg CpG Days 2, 3, 4, 6 & 8), untreated tumors regressed just as well as CpG-treated tumors indicating a systemic anti-tumor immune response was generated. Conclusion: Anti-idiotype therapy, although effective in delaying tumor growth, frequently generates antigen-loss variants. However, we found that when anti-idiotype antibodies were combined with CpG, even large established tumors were cured due to systemic CD8+ T cell-dependent tumor immunity. Rather than simply mediating ADCC against a single tumor antigen, which requires the constant infusion of antibody to hamper tumor growth, we hypothesize a cytotoxic T-cell response against many tumor antigens was also generated. Such a diverse T-cell repertoire can prevent the emergence of tumor escapees and collectively provide long-lasting tumor protection. These pre-clinical results suggest that anti-tumor antibodies combined with CpG warrant further study in patients with B cell lymphoma.

SOX2 as a target for immunotherapy of pediatric gliomas.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. e22012-e22012 ◽  
Author(s):  
Juan Vasquez ◽  
Anita Huttner ◽  
Lin Zhang ◽  
Asher Marks ◽  
Amy Chan ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Tumor Cells ◽  
Tumor Immunity ◽  
Immune Checkpoint ◽  
Cell Mass ◽  
Immune Checkpoint Blockade ◽  
Checkpoint Blockade ◽  
Low Grade ◽  
Glial Tumors

e22012 Background: New treatments are needed to improve outcomes for pediatric gliomas. Immune checkpoint inhibitors are effective therapies in tumors with a high mutation burden that express multiple neo-antigens. However, for pediatric tumors that carry few mutations, there is a need to identify new antigenic targets of anti-tumor immunity. SOX2 is an embryonal stem cell antigen implicated in the biology of glioma initiating cells. Expression of SOX2 by pediatric glial tumors, and the capacity of the immune system in these patients to recognize SOX2, has not been studied. Methods: We examined the expression of SOX2 on paraffin-embedded tissue from pediatric glial tumors (n = 30). The presence of T cell immunity to SOX2 was examined in both blood and tumor-infiltrating T cells using antigen-dependent cytokine and T cell proliferation assays (n = 15). The nature of tumor-infiltrating immune cells in glial tumors (n = 4) was analyzed using single cell mass cytometry. Results: SOX2 is expressed by tumor cells but not surrounding normal tissue in all low grade gliomas (n = 15), high grade gliomas (n = 7), ependymomas (n = 3) and in 60% of oligodendrogliomas (n = 5). T cells against SOX2 can be detected in blood and tumor tissue in 33% of patients. CD4 and CD8 tumor infiltrating T-cells display a higher proportion of PD-1 expression compared to circulating T cells (p < 0.05). Glial CD4 and CD8 T cells are enriched for tissue resident memory phenotype (TRM; CD45RO+, CD69+, CCR7-) and the expression of PD-1 is primarily on these TRM cells (p < 0.05). A subset of CD4 and CD8 TRM cells also co-express multiple inhibitory checkpoints including PD-L1 and TIGIT. Glial tumors also contain NK cells with reduced expression of lytic granzyme (p < 0.05). Conclusions: Our data demonstrate in vivo immunogenicity of SOX2, which is specifically overexpressed on pediatric glial tumor cells. Our data also suggest that the TRM subset of tumor-infiltrating T cells may be key targets for immune checkpoint blockade, and harnessing tumor immunity will likely require the combined targeting of multiple inhibitory checkpoints. Future efforts to target SOX2 with dendritic cell vaccines combined with immune checkpoint blockade could provide effective tumor immunity and improve outcomes in pediatric brain tumors.

scholarly journals Modulation of the immune microenvironment by tumor-intrinsic oncogenic signaling

2019 ◽  
Vol 219 (1) ◽  
Author(s):  
Kim Bich Nguyen ◽  
Stefani Spranger
Keyword(s):  
T Cells ◽  
Tumor Microenvironment ◽  
Tumor Cells ◽  
Cd8 T Cells ◽  
Critical Role ◽  
Tumor Control ◽  
Oncogenic Signaling ◽  
Patient Response ◽  
Combination Treatments ◽  
Preclinical And Clinical Studies

The development of cancer immunotherapies has been guided by advances in our understanding of the dynamics between tumor cells and immune populations. An emerging consensus is that immune control of tumors is mediated by cytotoxic CD8+ T cells, which directly recognize and kill tumor cells. The critical role of T cells in tumor control has been underscored by preclinical and clinical studies that observed that T cell presence is positively correlated with patient response to checkpoint blockade therapy. However, the vast majority of patients do not respond or develop resistance, frequently associated with exclusion of T cells from the tumor microenvironment. This review focuses on tumor cell–intrinsic alterations that blunt productive anti-tumor immune responses by directly or indirectly excluding effector CD8+ T cells from the tumor microenvironment. A comprehensive understanding of the interplay between tumors and the immune response holds the promise for increasing the response to current immunotherapies via the development of rational novel combination treatments.

scholarly journals Self-antigen–specific CD8+ T cell precursor frequency determines the quality of the antitumor immune response

2009 ◽  
Vol 206 (4) ◽  
pp. 849-866 ◽  
Author(s):  
Gabrielle A. Rizzuto ◽  
Taha Merghoub ◽  
Daniel Hirschhorn-Cymerman ◽  
Cailian Liu ◽  
Alexander M. Lesokhin ◽  
...  
Keyword(s):  
Immune Response ◽  
T Cells ◽  
T Cell ◽  
Cancer Immunotherapy ◽  
Tumor Immunity ◽  
Cd8 T Cells ◽  
Cd8 T Cell ◽  
Cell Precursor ◽  
Precursor Frequency ◽  
Self Antigen

A primary goal of cancer immunotherapy is to improve the naturally occurring, but weak, immune response to tumors. Ineffective responses to cancer vaccines may be caused, in part, by low numbers of self-reactive lymphocytes surviving negative selection. Here, we estimated the frequency of CD8+ T cells recognizing a self-antigen to be &lt;0.0001% (∼1 in 1 million CD8+ T cells), which is so low as to preclude a strong immune response in some mice. Supplementing this repertoire with naive antigen-specific cells increased vaccine-elicited tumor immunity and autoimmunity, but a threshold was reached whereby the transfer of increased numbers of antigen-specific cells impaired functional benefit, most likely because of intraclonal competition in the irradiated host. We show that cells primed at precursor frequencies below this competitive threshold proliferate more, acquire polyfunctionality, and eradicate tumors more effectively. This work demonstrates the functional relevance of CD8+ T cell precursor frequency to tumor immunity and autoimmunity. Transferring optimized numbers of naive tumor-specific T cells, followed by in vivo activation, is a new approach that can be applied to human cancer immunotherapy. Further, precursor frequency as an isolated variable can be exploited to augment efficacy of clinical vaccine strategies designed to activate any antigen-specific CD8+ T cells.

Vaccination with ΔCD40L or Flagellin Gene-Modified T Cells Activates Dendritic Cells In Vivo and Induces a Potent Anti-Tumor Immune Response

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 1909-1909
Author(s):  
Adham S Bear ◽  
Meghan M Turnis ◽  
Xiao-Tong Song ◽  
Russell Cruz ◽  
An Lu ◽  
...  
Keyword(s):  
Immune Response ◽  
T Cells ◽  
Dendritic Cells ◽  
Lymph Nodes ◽  
Tumor Cells ◽  
Cd8 T Cells ◽  
Lymphoid Tissues ◽  
Protective Effects ◽  
Facs Analysis

Abstract Abstract 1909 Introduction: Cancer vaccines have shown promise in small animal models of cancer, but have thus far been disappointing in clinical settings. Successful induction of a systemic and long-term anti-tumor immune response following vaccination is dependent on delivery of tumor-associated antigens to lymphoid tissues, in combination with the activation of professional antigen presenting cells (APCs). Here we describe a novel live T cell vaccine (TCV) that delivers antigenic peptides to secondary lymph nodes while simultaneously activating endogenous dendritic cells (DCs) through transgenic expression of CD40L or bacterial flagellin (fliC). Methods: To generate TCVs, murine splenocytes were isolated from wild-type type C57BL/6 mice. Following activation with anti-CD3/anti-CD28 microbeads, splenocytes were transduced with pRV2011-luciferase-IRES-Thy1.1, pRV2011-CD40L-IRES-Thy1.1 or pRV2011-fliC-IRES-Thy1.1 retrovirus. Analysis of TCV migration to lymphoid organs was performed by bioluminescence imaging for firefly luciferase. Following transduction with CD40L and fliC molecules, TCVs were measured for transduction efficiency (Thy1.1) and transgene expression using FACS analysis of CD40L or by Western blot, respectively. TCVs were subsequently pulsed with MHC class I-restricted epitopes for ovalbumin257-264 (SIINFEKL) or Trp2180-188 (SVYDFFVWL) peptides and injected intravenously at a dose of 1×107 TCVs per vaccination. To test the protective effects of TCVs, C57BL/6 mice were immunized at days 0 and 14 and then challenged with either 5×105 B16-OVA (for TCV-SIIN) or parental B16.F10 (for TCV-SVYD) melanoma tumor cells. To examine the ability of TCVs to eliminate established tumors, mice received B16-OVA or B16.F10 tumor cells followed by vaccination with TCVs on days 3, 9 and 15. Immunological studies were performed on a subset of mice (n=5 per group) to analyze induction of tumor-specific T cells using tetramer and IFN-g ELIspot assays. In vivo activation of lymph node DCs was performed by FACS analysis for CD11c+ DC co-expressing CD86 and I-A/I-E mouse MHC class II antibodies. Results: Following activation, TCVs were efficiently transduced with retrovirus (>85% CD40L) or expressed high levels of fliC. Bioluminescent imaging showed that luciferase-expressing TCVs rapidly migrated to lymphoid organs including the spleen and cervical and inguinal lymph nodes demonstrating the capacity of TCVs to co-localize with professional APCs. Importantly, irradiation (30 Gy) of TCVs completely abrogated migration and persistence highlighting the requirement for live TCVs. Next we examined whether TCV-CD40L or TCV-fliC could induce a protective immune response against B16 tumors. Administration of TCV-fliC-SIIN (OVA) and TCV-CD40L-SIIN primed peptide-specific CD8+ T cells, and led to decreased tumor growth and increased survival in mice subsequently challenged with B16-Ova (p<0.05). This response corresponded with a statistically significant (p<.05) increase in SIIN-specific CD8+ T cells as measured by tetramer FACS analysis and IFN-g ELIspot assays. Vaccination of mice with established tumors showed similar tumor suppression with both TCV designs (p<05). As OVA is a xenogenic antigen, we next examined whether TCVs pulsed with Trp2 peptide (SVYD) could induce similar protective effects. While vaccination with SVYD-pulsed T cells alone (no gene modification) did not inhibit tumor growth, expression of CD40L or fliC by TCV pulsed with Trp2 peptide suppressed B16.F10 tumor proliferation and increased survival in mice with pre-established tumors (p<.05). As found in the B16.OVA experiments, immunological protection correlated with a dramatic increase in SVYD-specific CD8+ T cells in the spleen, tumor draining lymph nodes and tumor. Conclusions: The efficient delivery of tumor-associated antigens to lymphoid tissues by TCVs overcomes a major limitation of alternative vaccine strategies. Vaccination with peptide-pulsed TCVs primes antigen-specific T cell responses with anti-tumor capability, and endogenous DC maturation leads to the inhibition of established B16-Ova and B16-F10 tumors. This illustrates the role of endogenous DC as mediators of the vaccine response and demonstrates the effectiveness of using TCVs to deliver antigen in the context of DC activating molecules. Disclosures: No relevant conflicts of interest to declare.

Variability in immune infiltrates and HLA expression in cholangiocarcinoma.

2014 ◽  
Vol 32 (3_suppl) ◽  
pp. 230-230 ◽  
Author(s):  
Francesco Sabbatino ◽  
Lucia Milham ◽  
Vikram Deshpande ◽  
Ioannis T. Konstantinidis ◽  
Andrew X. Zhu ◽  
...  
Keyword(s):  
Immune Response ◽  
T Cells ◽  
Tumor Cells ◽  
Cd8 T Cells ◽  
Antigen Processing ◽  
Selective Pressure ◽  
Hla Class I ◽  
Class I ◽  
Hla Class I Antigen ◽  
Infiltrating Lymphocytes

230 Background: Cholangiocarcinoma continues to have a dismal prognosis. The lack of effective therapy prompted us to determine whether patients develop an immune response against their own tumors. The aim of this study is to evaluate the CD8 infiltrate and expression of HLA class I antigen processing machinery (APM) components in cholangiocarcinoma. The HLA class I antigen processing machinery (APM) components play a crucial role in expression of HLA class I tumor antigen derived peptide complexes. These complexes mediate the recognition of tumor cells by cognate T cells. Defects in the expression of HLA class I APM components by tumor cells suggests that the infiltrating lymphocytes impose selective pressure on tumor cells. This selective pressure would facilitate the outgrowth of tumors by escaping T cell recognition. Methods: Retrospective review of clinicopathologic factors was performed for 18 peripheral cholangiocarcinomas. Formalin fixed, paraffin embedded tumors were evaluated for the content of lymphocyte infiltrates and for the expression of HLA class I APM components. Results: Eighteen patients underwent a partial hepatectomy for peripheral cholangiocarcinoma of whom 10 were female. Median age was 63yo. The majority of patients had node negative tumors (10/12). All tumors had lymphocytic infiltration. Median number of lymphocytes in the fibrous septae between tumor lobules was 42 CD8 T cells per 10 high power field, but only 4 CD8 T cells within tumor lobules. HLA class I APM components was defective and not detected in three tumors, all of which were poorly differentiated. HLA expression was down regulated in 9 tumors. HLA expression was in normal range in the remaining 6 tumors. Median overall survival has not been reached. Conclusions: Lymphocytic infiltrates were seen in all resected cholangiocarcinoma specimens. The loss of HLA class I APM component expression in cholangiocarcinoma suggests that infiltrating lymphocytes reflect a patient’s immune response to his/her tumor. This information provides a sound rationale to consider immunotherapy in the treatment of cholangiocarcinoma, specifically with antibodies to check point molecules which enhance patients’ immune response against his own tumors.

scholarly journals Generation of CD8+ T cell–mediated immunity against idiotype-negative lymphoma escapees

Blood ◽  
2009 ◽  
Vol 114 (20) ◽  
pp. 4477-4485 ◽  
Author(s):  
Bindu Varghese ◽  
Adam Widman ◽  
James Do ◽  
Behnaz Taidi ◽  
Debra K. Czerwinski ◽  
...  
Keyword(s):  
Immune Response ◽  
T Cells ◽  
T Cell ◽  
Tumor Cells ◽  
Cd8 T Cells ◽  
Antibody Therapy ◽  
B Cell Lymphoma ◽  
Cd8 T Cell ◽  
T Cell Response ◽  
Cell Mediated Immunity

AbstractWe investigated the ability of CpG-oligodeoxynucleotide to generate an anti-tumor CD8+ T-cell immune response and to synergize with passive antibody therapy. For these studies, we generated an antibody against the idiotype on the A20 B-cell lymphoma line. This antibody caused the regression of established tumors, but ultimately the tumors relapsed. The escaping surface IgG-negative tumor cells were resistant to both antibody-dependent cellular cytotoxicity and signaling-induced cell death. Addition of intratumoral CpG to antibody therapy cured large established tumors and prevented the occurrence of tumor escapees. The failure of the combination therapy in mice deficient for CD8+ T cells demonstrates the critical role of CD8+ T cells in tumor eradication. When mice were inoculated with 2 tumors and treated systemically with antibody followed by intratumoral CpG in just one tumor, both tumors regressed, indicating that a systemic immune response was generated. Although antibody therapy can eliminate tumor cells bearing the target antigen, it frequently selects for antigen loss variants. However, when a poly-specific T-cell response was generated against the tumor by intratumoral CpG, even large established tumors were cured. Such an immune response can prevent the emergence of antibody selected tumor escapees and provide long-lasting tumor protection.

scholarly journals Knockout of High-Mobility Group Box 1 in B16F10 Melanoma Cells Induced Host Immunity-Mediated Suppression of In Vivo Tumor Growth

2021 ◽  
Author(s):  
Kanako Yokomizo ◽  
Kayoko Waki ◽  
Miyako Ozawa ◽  
Keiko Yamamoto ◽  
Sachiko Ogasawara ◽  
...  
Keyword(s):  
T Cells ◽  
Tumor Microenvironment ◽  
Tumor Growth ◽  
Tumor Cells ◽  
Tumor Immunity ◽  
Cd8 T Cells ◽  
Immune Cells ◽  
High Mobility

Abstract High mobility group box 1 (HMGB1) has been reported as a damage-associated molecular pattern (DAMP) molecule that is released from damaged or dead cells and induces inflammation and subsequent innate immunity. However, the role of HMGB1 in the anti-tumor immunity is unclear since inflammation in the tumor microenvironment also contributes to tumor promotion and progression. In the present study, we established HMGB1-knockout clones from B16F10 and CT26 murine tumors by genome editing using the CRISPR/Cas9 system and investigated the role of HMGB1 in anti-tumor immunity. We found that 1) knockout of HMGB1 in the tumor cells suppressed in vivo, but not in vitro, tumor growth, 2) the suppression of the in vivo tumor growth was mediated by CD8 T cells, and 3) infiltration of CD8 T cells, macrophages and dendritic cells into the tumor tissues was accelerated in HMGB1-knockout tumors. These results demonstrated that knockout of HMGB1 in tumor cells converted tumors from poor infiltration of immune cells called “cold” to “immune-inflamed” or “hot” and inhibited in vivo tumor growth mediated by cytotoxic T lymphocytes. Infiltration of immune cells to the tumor microenvironment is an important step in the series known as the cancer immunity cycle. Thus, manipulation of tumor-derived HMGB1 might be applicable to improve the clinical outcomes of cancer immunotherapies, including immune checkpoint blockades and cancer vaccine therapies.

Sign in / Sign up

Export Citation Format

Share Document