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Effector CD4 and CD8 T cells and their role in the tumor microenvironment.

ABSTRACT: T cells in tumors-the so-called tumor infiltrating lymphocytes (TIL) have been studied intensively over the past years. Compelling evidence point to a clinical relevance for high numbers of T cells at the tumor site with CD8 memory T cells as a key denominator for overall survival (OS) in patients with colo-rectal cancer (CRC), and also for others solid cancers. These data goes hand in hand with studies of clonality of TIL showing the T cells among TIL are expanded clonally, and also that tumor specific T cells of CD4 as well as CD8 type are enriched at the tumor site. The tumor microenvironment is hostile to T cell function e.g., due to expression of enzymes that depletes the amino acids tryptophan and arginine, high concentration of tumor secreted lactate, and presence innate cells or regulatory T cells both with suppressive activity. Analyses of the specificity of TILs in melanoma demonstrate that quite few known antigens are in fact recognized by these cultures underscoring patient unique and/or mutated antigens may represent important target for recognition.

SUBMITTER: Hadrup S

PROVIDER: S-EPMC3717059 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Tumor-specific CD4+ T cells maintain effector and memory tumor-specific CD8+ T cells.

Project description:Immunotherapies that augment antitumor T cells have had recent success for treating patients with cancer. Here we examined whether tumor-specific CD4(+) T cells enhance CD8(+) T-cell adoptive immunotherapy in a lymphopenic environment. Our model employed physiological doses of tyrosinase-related protein 1-specific CD4(+) transgenic T cells-CD4(+) T cells and pmel-CD8(+) T cells that when transferred individually were subtherapeutic; however, when transferred together provided significant (p ? 0.001) therapeutic efficacy. Therapeutic efficacy correlated with increased numbers of effector and memory CD8(+) T cells with tumor-specific cytokine expression. When combined with CD4(+) T cells, transfer of total (naïve and effector) or effector CD8(+) T cells were highly effective, suggesting CD4(+) T cells can help mediate therapeutic effects by maintaining function of activated CD8(+) T cells. In addition, CD4(+) T cells had a pronounced effect in the early posttransfer period, as their elimination within the first 3 days significantly (p < 0.001) reduced therapeutic efficacy. The CD8(+) T cells recovered from mice treated with both CD8(+) and CD4(+) T cells had decreased expression of PD-1 and PD-1-blockade enhanced the therapeutic efficacy of pmel-CD8 alone, suggesting that CD4(+) T cells help reduce CD8(+) T-cell exhaustion. These data support combining immunotherapies that elicit both tumor-specific CD4(+) and CD8(+) T cells for treatment of patients with cancer.

| S-EPMC4283993 | biostudies-literature

NKG2D defines tumor-reacting effector CD8+ T cells within tumor microenvironment.

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| S-EPMC8409295 | biostudies-literature

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| S-EPMC6794477 | biostudies-literature

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mTOR-dependent translation drives tumor infiltrating CD8+ effector and CD4+ Treg cells expansion.

Project description:We performed a systematic analysis of the translation rate of tumor-infiltrating lymphocytes (TILs) and the microenvironment inputs affecting it, both in humans and in mice. Measurement of puromycin incorporation, a proxy of protein synthesis, revealed an increase of translating CD4+ and CD8+ cells in tumors, compared to normal tissues. High translation levels are associated with phospho-S6 labeling downstream of mTORC1 activation, whereas low levels correlate with hypoxic areas, in agreement with data showing that T cell receptor stimulation and hypoxia act as translation stimulators and inhibitors, respectively. Additional analyses revealed the specific phenotype of translating TILs. CD8+ translating cells have enriched expression of IFN-γ and CD-39, and reduced SLAMF6, pointing to a cytotoxic phenotype. CD4+ translating cells are mostly regulatory T cells (Tregs) with enriched levels of CTLA-4 and Ki67, suggesting an expanding immunosuppressive phenotype. In conclusion, the majority of translationally active TILs is represented by cytotoxic CD8+ and suppressive CD4+ Tregs, implying that other subsets may be largely composed by inactive bystanders.

| S-EPMC8598161 | biostudies-literature

Targeting VEGFR2 with Ramucirumab strongly impacts effector/ activated regulatory T cells and CD8+ T cells in the tumor microenvironment.

Project description:BACKGROUND:Several studies have established a correlation between the VEGF-VEGFR2 axis and an immunosuppressive microenvironment; this immunosuppression can be overcome by anti-angiogenic reagents, such as ramucirumab (RAM). However, little is known about the immunological impact of anti-angiogenic reagents within the tumor microenvironment in human clinical samples. This study aimed at investigating the effects of RAM on the tumor microenvironmental immune status in human cancers. METHODS:We prospectively enrolled 20 patients with advanced gastric cancer (GC) who received RAM-containing chemotherapy. We obtained paired samples from peripheral blood mononuclear cells (PBMCs) and tumor-infiltrating lymphocytes (TILs) in primary tumors both pre- and post-RAM therapy to assess immune profiles by immunohistochemistry and flow cytometry. RESULTS:Within the tumor microenvironment, both PD-L1 expression and CD8+ T-cell infiltration increased after RAM-containing therapies. In addition, CD45RA-FOXP3highCD4+ cells (effector regulatory T cells [eTreg cells]) and PD-1 expression by CD8+ T cells were significantly reduced in TILs compared with PBMCs after RAM-containing therapies. Patients with partial response and longer progression-free survival had significantly higher pre-treatment eTreg frequencies in TILs than those with progressive disease. In in vitro analysis, VEGFR2 was highly expressed by eTreg cells. Further, VEGFA promoted VEGFR2+ eTreg cell proliferation, and this effect could be inhibited by RAM. CONCLUSIONS:This study suggests that the frequency of eTreg cells in TILs could be a biomarker for stratifying clinical responses to RAM-containing therapies. Further, we propose that RAM may be employed as an immuno-modulator in combination with immune checkpoint blockade.

| S-EPMC6186121 | biostudies-literature

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Project description:Chemokine-driven interactions of immune cells are essential for effective antitumor immunity. Human natural killer (NK) cells can be primed by the interleukin (IL)-1-related proinflammatory cytokine IL-18 for unique helper activity, which promotes dendritic cell (DC) activation and DC-mediated induction of type-1 immune responses against cancer. Here, we show that such IL-18-primed "helper" NK cells produce high levels of the immature DC (iDC)-attracting chemokines CCL3 and CCL4 upon exposure to tumor cells or the additional inflammatory signals IFN-?, IL-15, IL-12, or IL-2. These "helper" NK cells potently attract iDCs in a CCR5-dependent mechanism and induce high DC production of CXCR3 and CCR5 ligands (CXCL9, CXCL10, and CCL5), facilitating the subsequent recruitment of type-1 effector CD8(+) T (Teff) cells. Using cells isolated from the malignant ascites of patients with advanced ovarian cancer, we show that "helper" NK cell-inducing factors can be used to enhance local production of Teff cell-recruiting chemokines. Our findings reveal the unique chemokine expression profile of "helper" NK cells and highlight the potential for using two-signal-activated NK cells to promote homing of type-1 immune effectors to the human tumor environment.

| S-EPMC3780558 | biostudies-literature

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Project description:CD4 T cell help is critical to sustain effector CD8 T cell responses during chronic infection, notably via T follicular helper (Tfh)-derived interleukin-21 (IL-21). Conversely, CD4 depletion results in severe CD8 T cell dysfunction and lifelong viremia despite CD4 T cell reemergence following transient depletion. These observations suggest that repopulating CD4 subsets are functionally or numerically insufficient to orchestrate a robust CD8 response. We utilize spatial transcriptomics and single-cell RNA sequencing (scRNA-seq) to investigate CD4 T cell heterogeneity under CD4-replete and -deplete conditions and explore cellular interactions during chronic infection. Although IL-21-producing Tfh cells repopulate following transient CD4 depletion, they are outnumbered by immunomodulatory CD4 T cells. Moreover, the splenic architecture appears perturbed, with decreases in white pulp regions, coinciding with germinal center losses. These disruptions in splenic architecture are associated with diminished Tfh and progenitor CD8 T cell colocalization, providing a potential mechanism for impaired progenitor-to-effector CD8 T cell differentiation during "un-helped" conditions.

| S-EPMC9792173 | biostudies-literature

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Project description:The immune microenvironment in hepatocellular carcinoma (HCC), especially T-cell infiltration, plays a key role in the prognosis and drug sensitivity of HCC. Our study aimed to analyze genes related to non-regulatory CD4+ and CD8+ T cell in HCC. Data of HCC samples were downloaded from The Cancer Genome Atlas (TCGA) database. According to stromal and immune score retrieved by Estimation of Stromal and Immune cells in Malignant Tumor tissues using Expression data (ESTIMATE) algorithm, differentiated expressed genes (DEGs) between high and low stromal/immune scoring groups were collected. Using Cibersort algorithm, abundance of immune cells was calculated and genes related with CD4+ and CD8+ T cells were selected. Protein-protein interaction (PPI) networks and networks of microRNA (miRNA)-target gene interactions were illustrated, in which CD4+ and CD8+ T cell-related core genes were selected. Finally, Cox regression test and Kaplan-Meier (K-M) survival analysis were conducted. Totally, 1579 DEGs were identified, where 103 genes and 407 genes related with CD4+ and CD8+ T cell were selected, respectively. Each of 30 core genes related to CD4+ T cells and CD8+ T cells were selected by PPI network. Four genes each related with the two types of T cells had a significant impact on prognosis of HCC patients. Amongst, KLRB1 and IL18RAP were final two genes related to both two kinds of T cells and associated with overall survival of the HCC patients.

| S-EPMC9470630 | biostudies-literature

Human TCR-alpha beta+ CD4- CD8- T cells can derive from CD8+ T cells and display an inflammatory effector phenotype.

Project description:The origin and function of human double negative (DN) TCR-alphabeta+ T cells is unknown. They are thought to contribute to the pathogenesis of systemic lupus erythematosus because they expand and accumulate in inflamed organs. In this study, we provide evidence that human TCR-alphabeta+ CD4- CD8- DN T cells can derive from activated CD8+ T cells. Freshly isolated TCR-alphabeta+ DN T cells display a distinct gene expression and cytokine production profile. DN cells isolated from peripheral blood as well as DN cells derived in vitro from CD8+ T cells produce a defined array of proinflammatory mediators that includes IL-1beta, IL-17, IFN-gamma, CXCL3, and CXCL2. These results indicate that, upon activation, CD8+ T cells have the capacity to acquire a distinct phenotype that grants them inflammatory capacity.

| S-EPMC2878279 | biostudies-literature

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