scholarly journals Targeting the ERβ/HER Oncogenic Network in KRAS Mutant Lung Cancer Modulates the Tumor Microenvironment and Is Synergistic with Sequential Immunotherapy

2021 ◽  
Vol 23 (1) ◽  
pp. 81
Author(s):  
Abdulaziz A. Almotlak ◽  
Mariya Farooqui ◽  
Adam C. Soloff ◽  
Jill M. Siegfried ◽  
Laura P. Stabile
Keyword(s):  
Lung Cancer ◽  
T Cells ◽  
Tumor Microenvironment ◽  
Lung Adenocarcinoma ◽  
Cd8 T Cells ◽  
Immune Cells ◽  
Cell Activity ◽  
Oncogenic Signaling ◽  
Murine Bone Marrow

High ERβ/HER oncogenic signaling defines lung tumors with an aggressive biology. We previously showed that combining the anti-estrogen fulvestrant with the pan-HER inhibitor dacomitinib reduced ER/HER crosstalk and produced synergistic anti-tumor effects in immunocompromised lung cancer models, including KRAS mutant adenocarcinoma. How this combination affects the tumor microenvironment (TME) is not known. We evaluated the effects of fulvestrant and dacomitinib on murine bone marrow-derived macrophages (BMDMs) and CD8+ T cells, and tested the efficacy of the combination in vivo, using the KRAS mutant syngeneic lung adenocarcinoma model, FVBW-17. While this combination synergistically inhibited proliferation of FVBW-17 cells, it had unwanted effects on immune cells, by reducing CD8+ T cell activity and phagocytosis in BMDMs and inducing PD-1. The effects were largely attributed to dacomitinib, which caused downregulation of Src family kinases and Syk in immune cells. In a subcutaneous flank model, the combination induced an inflamed TME with increased myeloid cells and CD8+ T cells and enhanced PD-1 expression in the splenic compartment. Concomitant administration of anti-PD-1 antibody with fulvestrant and dacomitinib was more efficacious than fulvestrant plus dacomitinib alone. Administering anti-PD-1 sequentially after fulvestrant plus dacomitinib was synergistic, with a two-fold greater tumor inhibitory effect compared to concomitant therapy, in both the flank model and in a lung metastasis model. Sequential triple therapy has potential for treating lung cancer that shows limited response to current therapies, such as KRAS mutant lung adenocarcinoma.

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.

scholarly journals Id1 and PD-1 Combined Blockade Impairs Tumor Growth and Survival of KRAS-mutant Lung Cancer by Stimulating PD-L1 Expression and Tumor Infiltrating CD8+ T Cells

Cancers ◽  
2020 ◽  
Vol 12 (11) ◽  
pp. 3169
Author(s):  
Iosune Baraibar ◽  
Marta Roman ◽  
María Rodríguez-Remírez ◽  
Inés López ◽  
Anna Vilalta ◽  
...  
Keyword(s):  
Lung Cancer ◽  
T Cells ◽  
Tumor Growth ◽  
Lung Adenocarcinoma ◽  
Tumor Cells ◽  
Cd8 T Cells ◽  
Checkpoint Inhibitors ◽  
Combined Therapy ◽  
Tumor Infiltration

The use of PD-1/PD-L1 checkpoint inhibitors in advanced NSCLC is associated with longer survival. However, many patients do not benefit from PD-1/PD-L1 blockade, largely because of immunosuppression. New immunotherapy-based combinations are under investigation in an attempt to improve outcomes. Id1 (inhibitor of differentiation 1) is involved in immunosuppression. In this study, we explored the potential synergistic effect of the combination of Id1 inhibition and pharmacological PD-L1 blockade in three different syngeneic murine KRAS-mutant lung adenocarcinoma models. TCGA analysis demonstrated a negative and statistically significant correlation between PD-L1 and Id1 expression levels. This observation was confirmed in vitro in human and murine KRAS-driven lung cancer cell lines. In vivo experiments in KRAS-mutant syngeneic and metastatic murine lung adenocarcinoma models showed that the combined blockade targeting Id1 and PD-1 was more effective than each treatment alone in terms of tumor growth impairment and overall survival improvement. Mechanistically, multiplex quantification of CD3+/CD4+/CD8+ T cells and flow cytometry analysis showed that combined therapy favors tumor infiltration by CD8+ T cells, whilst in vivo CD8+ T cell depletion led to tumor growth restoration. Co-culture assays using CD8+ cells and tumor cells showed that T cells present a higher antitumor effect when tumor cells lack Id1 expression. These findings highlight that Id1 blockade may contribute to a significant immune enhancement of antitumor efficacy of PD-1 inhibitors by increasing PD-L1 expression and harnessing tumor infiltration of CD8+ T lymphocytes.

scholarly journals 708 Novel ways to exploit IL-21 to augment adoptive T cell transfer therapy against tumors

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A737-A737
Author(s):  
Anna Cole ◽  
Guillermo Rangel RIvera ◽  
Aubrey Smith ◽  
Megan Wyatt ◽  
Brandon Ware ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Immune Cells ◽  
Striking Difference ◽  
T Cell Therapy ◽  
Cell Immunity ◽  
Emory University

BackgroundIL-21 enhances the anti-tumor capacity of adoptively transferred CD8+ T cells, while IL-2 and IL-15 impair T cell immunity by driving their expansion to a more differentiated status. Yet, these cytokines can act on many different immune cells. Given the potency of IL-21, we tested if this cytokine directly augments T cells or rather if it enhances other immune cells in the culture that indirectly improves T cell therapy.MethodsTo test this question, splenocytes from pmel-1 transgenic mice were used, as all CD8+ T cells express a transgenic TCR specific for tumor-antigen gp10025–33 overexpressed on melanoma. We then peptide activated naïve CD8+ T cells enriched or not from the spleen of pmel-1 mice and expanded them in the presence of IL-21 or IL-2 (10 ng/mL) for four days. Expanded pmel-1 from these various cultures were then restimulated with irradiated splenocytes pulsed with gp10025–33 and grown an additional seven days with IL-2 (10 ng/mL), irrespective of their initial cytokine condition. The in vitro memory phenotype, exhaustion profile, and cytokine secretion of these cultures were then assayed. Furthermore, mice bearing B16KVP melanoma tumors were infused with pmel-1 T cells expanded via these various approaches and compared for their relative capacity to engraft, persist, and regress tumor in vivo.ResultsInterestingly, we discovered that IL-21-treated T cells generated from bulk splenocytes are phenotypically and functionally distinct from IL-21-treated isolated T cells. Upon restimulation, IL-21-treated T cells from bulk splenocytes exhibited an exhausted phenotype that was like anergic IL-2-treated T cells. Moreover, few cells expressed CD62L but expressed heightened markers of suppression, including TIM3, PD-1, and EOMES. Moreover, they produced more effector molecules, including granzyme B and IFN-gamma. In vivo IL-21-treated T cells expanded from bulk splenocytes engrafted and persisted poorly, in turn mediating suboptimal regression of melanoma. Conversely, IL-21 dramatically bolstered the engraftment and antitumor activity of T cells only if they were first isolated from the spleen prior to their expansion and infusion into the animal.ConclusionsCollectively, our data shows that IL-21 may improve ACT therapy best when used directly on antitumor CD8+ T cells. Further studies will illuminate the mechanism behind this striking difference and determine whether other cell subsets reactive to IL-21 cause T cell dysfunction and/or reduced bioavailability. These findings are important for defining the best culture conditions in which to use IL-21 for ACT.AcknowledgementsWe would like to acknowledge Emory University, The Winship Cancer Institute, and the Pediatrics/Winship Flow Cytometry Core.Ethics ApprovalAll animal procedures were approved by the Institutional Animal Care and Use Committee of Emory University, protocol number 201900225.

scholarly journals The critical immunosuppressive effect of MDSC-derived exosomes in the tumor microenvironment

2020 ◽  
Author(s):  
Mohammad H. Rashid ◽  
Thaiz F. Borin ◽  
Roxan Ara ◽  
Raziye Piranlioglu ◽  
Bhagelu R. Achyut ◽  
...  
Keyword(s):  
T Cells ◽  
Tumor Microenvironment ◽  
Tumor Growth ◽  
Cd8 T Cells ◽  
Suppressor Cells ◽  
Cell Types ◽  
Biological Macromolecules

AbstractMyeloid-derived suppressor cells (MDSCs) are an indispensable component of the tumor microenvironment (TME), and our perception regarding the role of MDSCs in tumor promotion is attaining extra layer of intricacy in every study. In conjunction with MDSC’s immunosuppressive and anti-tumor immunity, they candidly facilitate tumor growth, differentiation, and metastasis in several ways that yet to be explored. Alike any other cell types, MDSCs also release a tremendous amount of exosomes or nanovesicles of endosomal origin and partake in intercellular communications by dispatching biological macromolecules. There has not been any experimental study done to characterize the role of MDSCs derived exosomes (MDSC exo) in the modulation of TME. In this study, we isolated MDSC exo and demonstrated that they carry a significant amount of proteins that play an indispensable role in tumor growth, invasion, angiogenesis, and immunomodulation. We observed higher yield and more substantial immunosuppressive potential of exosomes isolated from MDSCs in the primary tumor area than those are in the spleen or bone marrow. Our in vitro data suggest that MDSC exo are capable of hyper activating or exhausting CD8 T-cells and induce reactive oxygen species production that elicits activation-induced cell death. We confirmed the depletion of CD8 T-cells in vivo by treating the mice with MDSC exo. We also observed a reduction in pro-inflammatory M1-macrophages in the spleen of those animals. Our results indicate that immunosuppressive and tumor-promoting functions of MDSC are also implemented by MDSC-derived exosomes which would open up a new avenue of MDSC research and MDSC-targeted therapy.

Low TWEAK expression indicates poor survival and is correlated with sparse TIICs in lung adenocarcinoma (LUAD).

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e21017-e21017
Author(s):  
Jinchun Wu ◽  
Xianyu Liu ◽  
Yanhua Mou ◽  
Shan Zeng ◽  
Jin Zhang ◽  
...  
Keyword(s):  
T Cells ◽  
Lung Adenocarcinoma ◽  
Cd8 T Cells ◽  
Immune Cells ◽  
Poor Prognosis ◽  
Immune Escape ◽  
Underlying Mechanism ◽  
Memory Cd8 T Cells ◽  
Kaplan Meier ◽  
Kaplan Meier Plotter

e21017 Background: Lung adenocarcinoma (LUAD) occupies the most of non-small cell lung cancer (NSCLC) and shows promising response to PD-1 immunotherapy, but immune escape will cause treatment failure indicating poor prognosis. TWEAK (Tumor necrosis factor-related weak inducer of apoptosis, also known as TNFSF12) combining with its receptor FN14 (fibroblast growth factor–inducible 14) mediates crucial innate and adaptive immune pathways to promote the progression of multiple autoimmune diseases. So we assumed that TWEAK is a prognostic predictor and related with tumor-infiltrating immune cells (TIICs) in LUAD. Methods: TWEAK expression of LUAD was primarily investigated in The Cancer Immunome Atlas (TCIA) and then validated in Tumor Immune Estimation Resource (TIMER) databases. We assessed the effect of TWEAK on the survival via the Kaplan-Meier plotter, GEPIA2 (gene expression profiling interactive analysis) and PrognoScan databases. The relation between TWEAK and TIICs was explored in TIMER and TCIA, as well as the correlation of TWEAK and FN14 was analyzed in TIMER and GEPIA2. Results: Low TWEAK expression was significantly associated with poor relapse-free survival (RFS) (HR = 0.62, 95% CI = 0.4~0.97, logrank P = 0.035) and overall survival (OS) (HR = 0.61, 95% CI = 0.46~0.83, logrank P = 0.0012) in LUAD from Kaplan-Meier plotter. Similar impacts of TWEAK on the survival were validated in GEPIA2 and four independent cohorts from PrognoScan (jacob-00182-CANDF, GSE13213, jacob-00182-MSK and GSE31210). Moreover, reduced TWEAK expression was closely related with the paucity of TIICs which contributed to poor OS, including central memory CD8 T cells, plasmacytoid dendritic cells, activated CD8 T cells, monocytes, T follicular helper cells, immature B cells and eosinophils. In addition, TWEAK expression was positively related with the expression level of FN14 in both GEPIA2(R = 0.13, P= 0.0031) and TIMER (partial.cor = 0.212, P= 2.04e-06). Conclusions: Low TWEAK expression maybe indicate poor prognosis in LUAD, and correlated with the impaired infiltration of immune cells in the tumor region. The defective TWEAK/FN14 pathway possibly accounts for these observations, but the underlying mechanism needs to be further explored.

scholarly journals CD155/CD96 promotes immunosuppression in lung adenocarcinoma (LUAD)

2019 ◽  
Author(s):  
Weiling He ◽  
Hui Zhang ◽  
Shuhua Li ◽  
Yongmei Cui ◽  
Ying Zhu ◽  
...  
Keyword(s):  
Immune Response ◽  
T Cells ◽  
Tumor Microenvironment ◽  
Lung Adenocarcinoma ◽  
Cd8 T Cells ◽  
Immune Suppression ◽  
Sodium Dodecyl ◽  
Antitumor Immune Response ◽  
Patient Derived Xenograft ◽  
Poliovirus Receptor

AbstractLung adenocarcinoma (LUAD) remains one of the leading causes of death in patients with cancer. The association of CD155 with CD96 transmits an inhibitory signal and suppresses antitumor immune response. This study investigates the effect of CD155/CD96 on immune suppression in LUAD. We demonstrate that LUAD patients with high CD155 expression suffer from immune suppression and experience a poor prognosis, which coincides with an inhibited AKT-mTOR signaling pathway in CD8 T cells and subsequently up-regulated CD96 expression. Moreover, the inhibition effect can be reversed by CD96 blocking antibody. High CD155 expression inhibited the release of IFNγ from CD8 cells. Moreover, Blocking CD96 restored IFNγ production in CD8 T cells and neutralized the inhibition of IFNγ production in CD8 T cells mediated by CD155. Animal experiments showed that CD155-mediated LUAD growth might depend on its suppression antitumor immune response in the tumor microenvironment in PDX mice. In conclusion, our results suggest that LUAD cells suppress antitumor immune response in the tumor microenvironment through CD155/CD96. CD155/CD96 could be a potential therapeutic target for LUAD patients.AbbreviationsLUAD: lung adenocarcinoma; IFNγ: interferon gamma; PDX: patient-derived xenograft; NSCLC: non-small cell lung cancer; PRR: poliovirus receptor–related; MDSCs: myeloid-derived suppressor cells; PRR: poliovirus receptor–related; STR: short tandem repeat; IRS: immunoreactive score; SI: staining intensity; PP: percentage of positive cells; RT-PCR: reverse transcription-polymerase chain reaction; PBS: phosphate-buffered saline; PBMCs: peripheral blood mononuclear cells; SDS–PAGE: sodium dodecyl sulfate-polyacrylamide gel electrophoresis; rCD155: recombinant human CD155; LUAD cells: lung adenocarcinoma cells; TILs: tumor-infiltrating lymphocytes; GzmB: granzyme B; IL-2 (Interleukin-2); TNF-α : tumor necrosis factor-alpha; PI: propidium Iodide; PDX: patient-derived xenograft; TIGIT: T cell immunoreceptor with Igand ITIM domains; WBC: white blood cells; MFI: mean fluorescence intensity; HPF: high power field

scholarly journals CENPF driven lung adenocarcinoma and lung squamous cell carcinoma with immune infiltrates

2020 ◽  
Author(s):  
Lei Li ◽  
Pengchao Zheng
Keyword(s):  
Lung Cancer ◽  
Squamous Cell Carcinoma ◽  
T Cells ◽  
B Cells ◽  
Lung Adenocarcinoma ◽  
Cell Carcinoma ◽  
Squamous Cell ◽  
Cd8 T Cells ◽  
Lung Squamous Cell Carcinoma ◽  
Gene Marker

Abstract Background: CENPF (centromere protein F) is a critical gene that associates with the centromere-kinetochore complex and plays an important role in the tumor development. However, the associations of CENPF expression and tumor infiltrating lymphocytes in lung cancer remain unknown. Methods : CENPF expression and prognostic factor was analyzed via the Gene Expression Profiling Interactive Analysis (GEPIA) site. The correlation between CENPF and cancer immune infiltrates was investigated via and Tumor Immune Estimation Resource (TIMER) site. Further, correlations between CENPF expression and gene marker sets of immune infiltrates were analyzed by TIMER. Results: The TCGA database of Lung adenocarcinoma(LUAD) and Lung squamous cell carcinoma(LUSC) patients showed that high CENPF expression was associated with poorer overall survival (OS HR=1.5,P=0.01) and disease-free survival (DFS HR=1.4,P=0.027) in LUAD. Specifically, high CENPF expression have no correlated with worse OS(OS HR=0.78,P=0.071) and DFS(DFS HR=1,P=0.87) in LUSC. CENPF expression was positively correlated with infiltrating levels of B cells, macrophage in LUAD, B cells, and CD8+ T cells, macrophages, neutrophils, and dendritic cells (DCs) in LUSC. CENPF expression showed strong correlations with diverse immune marker sets in LUAD, and LUSC. After down-regulating the expression of CENPF, the proliferative capacity of Lung adenocarcinoma and Lung squamous cell carcinoma cells was inhibited. Conclusions: This report suggest that CENPF is high expression, correlated with poor prognosis and immune infiltrating levels of, including those of B cells, CD8+ T cells, CD4+ T cells, macrophages, neutrophils, and DCs in in LUAD and LUSC. In addition, CENPF expression is potentially closely related to the proliferation and metastasis of lung cancer cells. These studies suggest that CENPF can be used as a new prognostic target for determining prognosis and immune infiltration in Lung adenocarcinoma and Lung squamous cell carcinoma.

scholarly journals CENPF driven lung adenocarcinoma and lung squamous cell carcinoma with immune infiltrates

2020 ◽  
Author(s):  
Lei Li ◽  
Pengfei Zheng
Keyword(s):  
Lung Cancer ◽  
Squamous Cell Carcinoma ◽  
T Cells ◽  
B Cells ◽  
Lung Adenocarcinoma ◽  
Cell Carcinoma ◽  
Squamous Cell ◽  
Cd8 T Cells ◽  
Lung Squamous Cell Carcinoma ◽  
Gene Marker

Abstract Background: CENPF (centromere protein F) is a critical gene that associates with the centromere-kinetochore complex and plays an important role in the tumor development. However, the associations of CENPF expression and tumor infiltrating lymphocytes in lung cancer remain unknown. Methods: CENPF expression and prognostic factor was analyzed via the Gene Expression Profiling Interactive Analysis (GEPIA) site. The correlation between CENPF and cancer immune infiltrates was investigated via and Tumor Immune Estimation Resource (TIMER) site. Further, correlations between CENPF expression and gene marker sets of immune infiltrates were analyzed by TIMER. Results: The TCGA database of Lung adenocarcinoma(LUAD) and Lung squamous cell carcinoma(LUSC) patients showed that high CENPF expression was associated with poorer overall survival (OS HR=1.5,P=0.01) and disease-free survival (DFS HR=1.4,P=0.027) in LUAD. Specifically, high CENPF expression have no correlated with worse OS(OS HR=0.78,P=0.071) and DFS(DFS HR=1,P=0.87) in LUSC. CENPF expression was positively correlated with infiltrating levels of B cells, macrophage in LUAD, B cells, and CD8+ T cells, macrophages, neutrophils, and dendritic cells (DCs) in LUSC. CENPF expression showed strong correlations with diverse immune marker sets in LUAD, and LUSC. After down-regulating the expression of CENPF, the proliferative capacity of Lung adenocarcinoma and Lung squamous cell carcinoma cells was inhibited. Conclusions: This report suggest that CENPF is high expression, correlated with poor prognosis and immune infiltrating levels of, including those of B cells, CD8+ T cells, CD4+ T cells, macrophages, neutrophils, and DCs in in LUAD and LUSC. In addition, CENPF expression is potentially closely related to the proliferation and metastasis of lung cancer cells. These studies suggest that CENPF can be used as a new prognostic target for determining prognosis and immune infiltration in Lung adenocarcinoma and Lung squamous cell carcinoma.

scholarly journals 661 Neoantigen-specific CD4+ T cells in human melanoma have diverse differentiation states and correlate with CD8+ T cell, macrophage, and B cell function

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A689-A689
Author(s):  
Naina Singhi ◽  
Carolyn Shasha ◽  
Sylvia Lee ◽  
Julia Szeto ◽  
Ata Moshiri ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Tumor Microenvironment ◽  
Cd8 T Cells ◽  
Immune Cells ◽  
Tumor Antigen ◽  
Cd4 T Cells ◽  
Viral Antigen ◽  
Tumor Antigens ◽  
Human Melanoma

BackgroundTumor-antigen specific CD4+ T cells are crucial for the efficacy of antibodies that block immune checkpoint proteins in mouse tumor models, but their activities in human tumor immunity are less clear. CD8+ T cells infiltrating human tumors, including those specific for tumor antigens, have been studied using single cell profiling techniques and exist in a variety of dysfunctional states. The transcriptional states of tumor-specific CD4+ T cells present in tumors and their potential contributions to the tumor microenvironment are less well understood.MethodsWe used targeted single cell RNA sequencing and matching of T cell receptor (TCR) sequences to identify phenotypic signatures that discriminated tumor antigen- and viral antigen-specific CD4+ T cells infiltrating human melanoma tumors in four patients. The presence of CD4+ T cells with these signatures was correlated with the number and phenotype of other immune cells in the tumor microenvironment in an extended cohort of 20 patients.ResultsWe identified 259 CD4+ T cells representing 40 different TCR clonotypes specific for 13 neoantigens and 108 cells representing 14 TCR clonotypes specific for self-antigens in four melanoma patients. High expression of CXCL13 defined conventional CD4+ T cells that recognize tumor associated neoantigens and self-antigens from bystander and viral antigen-specific CD4+ T cells. Tumor-reactive CD4+ T cells could be subdivided into clusters expressing memory and T follicular helper markers, and those expressing cytolytic markers and IFN-g. In an extended cohort of 20 patients with melanoma, the frequency of CXCL13+ CD4+ T cells in the tumor microenvironment correlated with the presence and proliferation of CD8+ T cells, the presence and maturation of B cells, the activation of interferon responsive genes in tumor associated macrophages, and patient survival. CD4+ T cells with similar transcriptional signatures were identified in data sets from breast and non-small cell lung cancer, suggesting these markers may enrich for tumor-reactive CD4+ T cells in many cancers.ConclusionsThese results identify a subset of tumor infiltrating conventional CD4+ T cells in melanoma that are enriched for reactivity to tumor antigens and exist in multiple phenotypic states. Correlations of the presence of these cells with the frequency and phenotype of other immune cells suggest roles for these tumor antigen-specific CD4+ T cells in providing CD8+ T cell help, driving recruitment and maturation of B cells, and activating macrophages. Isolating such cells based on their unique phenotype and utilizing them for adoptive therapy could alter the tumor microenvironment for therapeutic benefit.Ethics ApprovalAll Patient samples in this study were obtained from patients who signed informed consent in a study approved by the institutional review board of the Fred Hutchinson Cancer Research Center (protocol #2643).

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.

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