The Role of Checkpoint Inhibitors and Cytokines in Adoptive Cell-Based Cancer Immunotherapy with Genetically Modified T Cells

2019 ◽  
Vol 84 (7) ◽  
pp. 695-710 ◽  
Author(s):  
P. M. Gershovich ◽  
A. V. Karabelskii ◽  
A. B. Ulitin ◽  
R. A. Ivanov
Keyword(s):  
T Cells ◽  
Cancer Immunotherapy ◽  
Checkpoint Inhibitors ◽  
Genetically Modified

scholarly journals Fibroblastic reticular cells predict response to immune checkpoint inhibitors

2020 ◽  
Author(s):  
Daniele Biasci ◽  
James Thaventhiran ◽  
Simon Tavaré
Keyword(s):  
T Cells ◽  
B Cells ◽  
B Cell ◽  
Cancer Immunotherapy ◽  
Cd8 T Cells ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Reticular Cells

While the role of CD8+ T cells in mediating response to cancer immunotherapy is well established, the role of B cells remains more controversial (1–3). By conducting a large gene expression study of response to immune checkpoint inhibitors (ICI), we show that pre-treatment expression of B cell genes is associated with ICI response independently of CD8+ T cells. However, we discovered that such association can be completely explained by a single gene (FDCSP) expressed outside of the B cell compartment, in fibroblastic reticular cells (FRCs), which form the reticular network that facilitates interactions between B cells, T cells and cognate antigens (4–6) and are required to initiate efficient adaptive immune responses in secondary lymphoid organs (SLO) and tertiary lymphoid structures (TLS) (4, 7). We validated this finding in three independent cohorts of patients treated with ICI in melanoma and renal cell carcinoma. Taken together, these results suggest that FDCSP is an independent predictor of ICI response, thus opening new avenues to explain the mechanisms of resistance to cancer immunotherapy.

scholarly journals Repurposing Infectious Pathogen Vaccines in Cancer Immunotherapy

2020 ◽  
Author(s):  
Matteo Conti
Keyword(s):  
Cancer Immunotherapy ◽  
Checkpoint Inhibitors ◽  
Mouse Tumor ◽  
Combined Approach ◽  
Anticancer Immunotherapy ◽  
Intratumoral Delivery ◽  
Infectious Pathogen ◽  
Novel Strategy ◽  
Mouse Tumor Models

Reports in the literature show that certain vaccines against infectious pathogens, can be effective in eliciting antitumor immune response when injected intratumorally. In mouse tumor models, intratumoral delivery of rotavirus, yellow fever, and influenza vaccines have been shown to also synergize with checkpoint inhibitors, in the leading immunotherapy in the clinical practice today. The combined approach can thus become a very promising novel strategy for anticancer immunotherapy. In humans, an attenuated poliomyelitis virus vaccine, a peptide-based vaccines against papilloma and one based on detoxified diphtheria protein have already been tested as intratumoral treatments readily. In those studies, the role of available anti-pathogen immunity appears an important element in mediating the activity of the repurposed vaccines against cancer. We therefore suggest how evaluating or eventually developing anti-pathogen immunity before intratumoral delivery could be helpful in repurposing infectious pathogen vaccines in cancer immunotherapy.

ERO1L shapes the immune-suppressive tumor microenvironment and is a potential biomarker for immunotherapy response in lung adenocarcinoma.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e21006-e21006
Author(s):  
Lihui Liu ◽  
Chao Wang ◽  
Sini Li ◽  
Pei Xue ◽  
Hua Bai ◽  
...  
Keyword(s):  
T Cells ◽  
Endoplasmic Reticulum ◽  
Lung Adenocarcinoma ◽  
Signaling Pathways ◽  
Survival Data ◽  
Checkpoint Inhibitors ◽  
Q Value ◽  
Immune Infiltration ◽  
Potential Biomarker

e21006 Background: Recently, immune checkpoint inhibitors have led to a paradigm shift in treatment for patients with lung adenocarcinoma (LUAD), however, the identification of biomarkers to enable patient selection is urgently required. The endoplasmic reticulum oxidoreductin-1-like ( ERO1L) gene encodes an endoplasmic reticulum luminal localized glycoprotein known to associated with hypoxia. The role of ERO1L in the crafting of the tumor immune microenvironment (TIME) is yet to be elucidated. Methods: In this study, raw datasets (including RNA-seq, methylation, sgRNA-seq, phenotype, and survival data) were obtained from public databases. This data was analyzed and used to explore the biological landscape of ERO1L in immune infiltration. Expression data was used to characterize samples. Using gene signatures and cell quantification, stromal and immune infiltration was determined. These findings were used to predict sensitivity to immunotherapy. Results: We identified ERO1L to be an oncogene, the mRNA expression of which is significantly higher in LUAD compared with normal tissues. High expression levels of ERO1L were associated with poor prognoses in terms of overall survival (HR: 1.52, 95% CI: 1.27-1.82) and progression-free survival (HR: 1.93, 95% CI: 1.47-2.53). This overexpression was found to be a result of hypomethylation of the ERO1L promoter. Overexpression of ERO1L resulted in an immune-suppressive TIME via the recruitment of immune-suppressive cells including regulatory T cells (Spearman’s ρ = 0.199, p < 0.001) cancer associated fibroblasts (ρ = 0.286, p < 0.001), and myeloid-derived suppressor cells (ρ = 0.423, p < 0.001), and also indicated the polarization of M1-type to M2-type macrophage. On the contrary, overexpression of ERO1L was closely associated with deficiency of immune-active cells including B cells (ρ = -0.250, p < 0.001), CD8+ T cells (ρ = -0.299, p < 0.001), and NK cells (ρ = -0.258, p < 0.001). Using the Tumor Immune Dysfunction and Exclusion (TIDE) framework, it was identified that patients in the ERO1Lhigh group possessed a significantly lower response rate (31.0%) to immunotherapy compared with the ERO1Llow group (86.0%). Mechanistic analysis revealed that overexpression of ERO1L was associated with the upregulation of JAK-STAT (NES = 1.65, FDR q-value = 0.0) and NF-κB (NES = 2.03, FDR q-value = 0.0) signaling pathways, thus affecting chemokine and cytokine patterns in the TIME. Conclusions: Our study provides clear insight into the potential role of ERO1L in tumor immunology. Overexpression of ERO1L was indicative of a hypoxia-induced immune-suppressive TIME, which was shown to confer resistance to immunotherapy in patients with LUAD. ERO1L was shown to mediate cytokine and chemokine patterns in the TIME, which were resulted from activations of JAK-STAT and NF-κB signaling pathways.

Structure and functions of T-cell immunoglobulin-domain and mucin- domain protein 3 in cancer

2021 ◽  
Vol 28 ◽  
Author(s):  
Xinjie Lu
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cancer Immunotherapy ◽  
Intracellular Signaling ◽  
Checkpoint Inhibitors ◽  
Cell Types ◽  
Structural Features ◽  
Type I ◽  
Potential Biomarker ◽  
Tim Proteins

Background: T-cell immunoglobulin (Ig)-domain and mucin-domain (TIM) proteins represent a family of receptors expressed on T-cells that play essential cellular immunity roles. The TIM proteins span across the membrane belonging to type I transmembrane proteins. The N terminus contains an Ig-like V-type domain and a Ser/Thr-rich mucin stalk as a co-inhibitory receptor. The C-terminal tail oriented toward the cytosol predominantly mediates intracellular signaling. Methods: This review discusses the structural features and functions of TIM-3, specifically on its role in mediating immune responses in different cell types, and the rationale for TIM-3-targeted cancer immunotherapy. Results: TIM-3 has gained significant importance to be a potential biomarker in cancer immunotherapy. It has been shown that blockade with checkpoint inhibitors promotes anti-tumor immunity and inhibits tumor growth in several preclinical tumor models. Conclusion: TIM-3 is an immune regulating molecule expressed on several cell types, including IFNγ-producing T-cells, FoxP3+ Treg cells, and innate immune cells. The roles of TIM-3 in immunosuppression support its merit as a target for cancer immunotherapy.

scholarly journals Autoimmunity linked protein phosphatase PTPN22 as a target for cancer immunotherapy

2020 ◽  
Vol 8 (2) ◽  
pp. e001439 ◽  
Author(s):  
Rafael Cubas ◽  
Zia Khan ◽  
Qian Gong ◽  
Marina Moskalenko ◽  
Huizhong Xiong ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cancer Immunotherapy ◽  
Phosphatase Activity ◽  
Tumor Regression ◽  
Checkpoint Inhibitors ◽  
Therapeutic Option ◽  
Interleukin 2 ◽  
Cell Functions ◽  
Increased Risk

BackgroundCancer immunotherapy has evolved from interferon-alpha (IFNα) and interleukin-2 in the 1980s to CTLA-4 and PD-1/PD-L1 checkpoint inhibitors (CPIs), the latter highlighting the importance of enhancing T-cell functions. While the search for novel immunomodulatory pathways continues, combination therapies augmenting multiple pathways can also increase efficacy. The association of autoimmune-related adverse events with clinical efficacy following CPI treatment has been inferred and suggests that breaking tolerance thresholds associated with autoimmunity may affect host immune responses for effective cancer immunotherapy.ResultsHere, we show that loss of autoimmune associated PTPN22, a key desensitization node for multiple signaling pathways, including IFNα receptor (IFNAR) and T-cell receptor, can augment tumor responses. Implantation of syngeneic tumors in Ptpn22-/- mice led to expansion and activation of peripheral and intratumoral T cells and, in turn, spontaneous tumor regression as well as enhanced responses in combination with anti-PD-L1 treatment. Using genetically modified mice expressing a catalytically inactive PTPN22 or the autoimmunity-associated human single-nucleotide polymorphism variant, augmentation of antitumor immunity was dependent on PTPN22 phosphatase activity and partially on its adaptor functions. Further, antitumor responses were dependent on both CD4+ and CD8+T cells and, in part, IFNAR function. Finally, we demonstrate that the autoimmune susceptibility Ptpn22(C1858T) variant is associated with lower risk of developing non-melanoma skin cancers, improved overall survival and increased risk for development of hyperthyroidism or hypothyroidism following atezolizumab (anti-PD-L1) treatment.ConclusionsTogether, these data suggest that inhibition of PTPN22 phosphatase activity may provide an effective therapeutic option for cancer immunotherapy and that exploring genetic variants that shift immune tolerance thresholds may serve as a paradigm for finding new cancer immunotherapy targets.

scholarly journals The emerging role of γδ T cells in cancer immunotherapy

2019 ◽  
Vol 1 ◽  
pp. 3-10 ◽  
Author(s):  
Oliver Nussbaumer ◽  
Michael Koslowski
Keyword(s):  
T Cells ◽  
Cancer Immunotherapy ◽  
Γδ T Cells

scholarly journals Natural Killer Cells: The Linchpin for Successful Cancer Immunotherapy

2021 ◽  
Vol 12 ◽  
Author(s):  
Kari A. Shaver ◽  
Tayler J. Croom-Perez ◽  
Alicja J. Copik
Keyword(s):  
T Cells ◽  
Immune System ◽  
Nk Cells ◽  
Cancer Immunotherapy ◽  
Natural Killer ◽  
Nk Cell ◽  
Checkpoint Inhibitors ◽  
Cytotoxic T Cells ◽  
Current Evidence ◽  
Cell Therapies

Cancer immunotherapy is a highly successful and rapidly evolving treatment modality that works by augmenting the body’s own immune system. While various immune stimulation strategies such as PD-1/PD-L1 or CTLA-4 checkpoint blockade result in robust responses, even in patients with advanced cancers, the overall response rate is low. While immune checkpoint inhibitors are known to enhance cytotoxic T cells’ antitumor response, current evidence suggests that immune responses independent of cytotoxic T cells, such as Natural Killer (NK) cells, play crucial role in the efficacy of immunotherapeutic interventions. NK cells hold a distinct role in potentiating the innate immune response and activating the adaptive immune system. This review highlights the importance of the early actions of the NK cell response and the pivotal role NK cells hold in priming the immune system and setting the stage for successful response to cancer immunotherapy. Yet, in many patients the NK cell compartment is compromised thus lowering the chances of successful outcomes of many immunotherapies. An overview of mechanisms that can drive NK cell dysfunction and hinder immunotherapy success is provided. Rather than relying on the likely dysfunctional endogenous NK cells to work with immunotherapies, adoptive allogeneic NK cell therapies provide a viable solution to increase response to immunotherapies. This review highlights the advances made in development of NK cell therapeutics for clinical application with evidence supporting their combinatorial application with other immune-oncology approaches to improve outcomes of immunotherapies.

scholarly journals Targeting Pim2 for Improving T-Cell Effector Function and Promoting Cancer Immunotherapy

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 1720-1720
Author(s):  
Yongxia Wu ◽  
Linlu Tian ◽  
Corey Mealer ◽  
Hee-Jin Choi ◽  
Xue-Zhong Yu
Keyword(s):  
Breast Cancer ◽  
T Cells ◽  
T Cell ◽  
Cancer Immunotherapy ◽  
Cd8 T Cells ◽  
Cd8 T Cell ◽  
Effector Function ◽  
Cell Responses ◽  
Deficient Mice

Abstract The Provirus Integration sites for Moloney murine leukemia virus (Pim) kinases are a highly conserved family of serine/threonine kinases. The Pim kinase family is composed of three different isoforms, Pim1, Pim2, and Pim3, which have been studied extensively in tumorigenesis and as a potential therapeutic target in various cancers. We previously reported an unexpected role of Pim2 in negatively regulates T-cell responses to alloantigen and tumor (JCI, 2015, PMID: 29781812). However, the mechanisms by which Pim2 modulates T-cell responses remain largely undefined. In the current study, using genetic Pim2-deficient mouse, we demonstrated a key role of Pim2 in regulating T-cell hemostatic and anti-tumor responses in aging, hematopoietic cell transplantation (HCT), and antigen-specific adoptive T-cell therapy (ACT). We observed that Pim2 was critical for T cells to retain quiescent in aged mice, as thymic Treg development was impaired while effector T-cell differentiation in lymphoid organs, including Tc1/Th1, Tc17/Th17 and follicular helper T cells, was increased in Pim2-deficient mice, but not in Pim1/Pim3-deficient mice. Furthermore, Pim2-deficient mice were capable to completely eradicate syngeneic breast cancer (NT2.5) growth (Figure A). During antigen specific anti-tumor response, adoptively transferred Pim2 -/- CD8 T cells showed enhanced ability for controlling established NT2.5 breast cancer and B16 melanoma (Figure B, C). Mechanistically, loss of Pim2 promoted G1 to S phase cell-cycle progression while reduced apoptosis in CD8 T cells. Pim2 -/- CD8 T cells exhibited elevated effector cytokine production while maintained higher levels of CD62L expression, leading to superior effector function, persistence and anti-tumor activity. Reduced differentiation of exhausted and suppressive subsets were observed in Pim2 -/- CD8 T cells after being adoptively transferred in tumor-bearing mice. In addition, Pim2 deficiency was associated with a higher metabolic potential, reflected by increased glycolysis and oxidative phosphorylation, which was at least partially attributed to a decreased level of autophagy in Pim2 -/- CD8 T cells. To further evaluate the clinical translation potential, we applied a Pim2-specific inhibitor (JP11646) and found that blocking Pim2 improved graft-versus-leukemia activity after autologous HCT and also enhanced CD8 T-cell mediated anti-melanoma effects after ACT in mice (Figure B, C). Furthermore, blocking Pim2 using JP11646 promoted human CD8 T-cell response during polyclonal stimulation and enhanced expansion, effector function and tumor killing ability of human melanoma antigen-specific CD8 T cells (data not shown) and CD19 CAR-T cells (Figure D). Our work demonstrated that Pim2 is a potent and distinct regulator of differentiation and maintenance of T effector cells through modulating metabolism and autophagy. Specifically target Pim2 can serve as a novel strategy for improving cancer immunotherapy. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

scholarly journals Novel tumour antigens and the development of optimal vaccine design

2018 ◽  
Vol 6 (2) ◽  
pp. 31-47 ◽  
Author(s):  
Victoria A Brentville ◽  
Suha Atabani ◽  
Katherine Cook ◽  
Lindy G Durrant
Keyword(s):  
T Cells ◽  
Immune System ◽  
T Cell ◽  
Checkpoint Inhibitors ◽  
T Cell Responses ◽  
Tumour Cells ◽  
Great Promise ◽  
Cell Responses ◽  
Tumour Antigens

The interplay between tumours and the immune system has long been known to involve complex interactions between tumour cells, immune cells and the tumour microenvironment. The progress of checkpoint inhibitors in the clinic in the last decade has highlighted again the role of the immune system in the fight against cancer. Numerous efforts have been undertaken to develop ways of stimulating the cellular immune response to eradicate tumours. These interventions include the identification of appropriate tumour antigens as targets for therapy. In this review, we summarize progress in selection of target tumour antigen. Targeting self antigens has the problem of thymic deletion of high-affinity T-cell responses leaving a diminished repertoire of low-affinity T cells that fail to kill tumour cells. Thymic regulation appears to be less stringent for differentiation of cancer–testis antigens, as many tumour rejection antigens fall into this category. More recently, targeting neo-epitopes or post-translational modifications such as a phosphorylation or stress-induced citrullination has shown great promise in preclinical studies. Of particular interest is that the responses can be mediated by both CD4 and CD8 T cells. Previous vaccines have targeted CD8 T-cell responses but more recently, the central role of CD4 T cells in orchestrating inflammation within tumours and also differentiating into potent killer cells has been recognized. The design of vaccines to induce such immune responses is discussed herein. Liposomally encoded ribonucleic acid (RNA), targeted deoxyribonucleic acid (DNA) or long peptides linked to toll-like receptor (TLR) adjuvants are the most promising new vaccine approaches. These exciting new approaches suggest that the ‘Holy Grail’ of a simple nontoxic cancer vaccine may be on the horizon. A major hurdle in tumour therapy is also to overcome the suppressive tumour environment. We address current progress in combination therapies and suggest that these are likely to show the most promise for the future.

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