A high OXPHOS CD8 T cell subset is predictive of immunotherapy resistance in melanoma patients.
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ABSTRACT:
SUBMITTER: Li C
PROVIDER: S-EPMC8611729 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:PurposeProtein expression in formalin-fixed, paraffin-embedded tissue is routinely measured by IHC or quantitative fluorescence (QIF) on a handful of markers on a single section. Digital spatial profiling (DSP) allows spatially informed simultaneous assessment of multiple biomarkers. Here we demonstrate the DSP technology using a 44-plex antibody cocktail to find protein expression that could potentially be used to predict response to immune therapy in melanoma.Experimental Design: The NanoString GeoMx DSP technology is compared with automated QIF (AQUA) for immune marker compartment-specific measurement and prognostic value in non-small cell lung cancer (NSCLC). Then we use this tool to search for novel predictive markers in a cohort of 60 patients with immunotherapy-treated melanoma on a tissue microarray using a 44-plex immune marker panel measured in three compartments (macrophage, leukocyte, and melanocyte) generating 132 quantitative variables.ResultsThe spatially informed variable assessment by DSP validates by both regression and variable prognostication compared with QIF for stromal CD3, CD4, CD8, CD20, and PD-L1 in NSCLC. From the 132 variables, 11 and 15 immune markers were associated with prolonged progression-free survival (PFS) and overall survival (OS). Notably, we find PD-L1 expression in CD68-positive cells (macrophages) and not in tumor cells was a predictive marker for PFS, OS, and response.ConclusionsDSP technology shows high concordance with QIF and validates based on both regression and outcome assessment. Using the high-plex capacity, we found a series of expression patterns associated with outcome, including that the expression of PD-L1 in macrophages is associated with response.
| S-EPMC6744974 | biostudies-literature
Project description:Immunotherapy has emerged as an exciting strategy for cancer treatment. Therapeutic blockade of immune checkpoint regulators favors the ability of T cell responses to increase anti-tumor immunity. The cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) and programmed cell death-1 (PD-1) are two T cell-inhibitory receptors with independent mechanisms of action. Immune checkpoint inhibitors targeting either CTLA-4, PD-1 or its ligand PD-L1 are currently yielding promising results in terms of efficacy in several clinical studies with melanoma patients and are being developed and tested as immunotherapy agents for multiple cancer types. To date, no reliable predictors of activity and efficacy of immunotherapy have yet been identified or validated. Even so, determining which patients derive clinical benefit from immune checkpoint agents remains an important clinical question and efforts to identify predictive markers of response are ongoing. This article reviews the current potential predictive factors for CTLA-4 and PD-1/PD-L1 immune checkpoints inhibitors in melanoma.
| S-EPMC4583591 | biostudies-literature
Project description:Clinical and Molecular Heterogeneity in Patients with Innate Resistance to Anti-PD-1 and/or Anti-CTLA-4 Immunotherapy in Metastatic Melanoma Reveals Distinct Therapeutic Targets
| PRJEB45846 | ENA
Project description:Immunotherapy has revolutionized the therapeutic landscape of melanoma. In particular, checkpoint inhibition has shown to increase long-term outcome, and, in some cases, it can be virtually curative. However, the absence of clinically validated predictive biomarkers is one of the major causes of unpredictable efficacy of immunotherapy. Indeed, the availability of predictive biomarkers could allow a better stratification of patients, suggesting which type of drugs should be used in a certain clinical context and guiding clinicians in escalating or de-escalating therapy. However, the difficulty in obtaining clinically useful predictive biomarkers reflects the deep complexity of tumor biology. Biomarkers can be classified as tumor-intrinsic biomarkers, microenvironment biomarkers, and systemic biomarkers. Herein we review the available literature to classify and describe predictive biomarkers for checkpoint inhibition in melanoma with the aim of helping clinicians in the decision-making process. We also performed a meta-analysis on the predictive value of PDL-1.
| S-EPMC8070445 | biostudies-literature
Project description:Specific mechanisms by which tumor-infiltrating lymphocytes (TIL) become dysfunctional remain poorly understood. Here, we employed a two-pronged approach using single-cell mass cytometry and tissue imaging technologies to dissect TILs from 25 patients with resectable and 35 patients with advanced non-small cell lung cancer (NSCLC). We identified a burned-out CD8+ TIL subset (Ebo) that specifically accumulated within the tumor microenvironment (TME) but not in adjacent nontumoral tissues. Ebo showed the highest expression of proliferation and activation markers but produced the lowest amount of IFNγ and were the most apoptotic CD8+ TIL subset. Using a humanized patient-derived tumor xenograft model, we demonstrated that Ebo expansion occurred within the TME in a PD-1/B7-H1 pathway-dependent manner. Ebo abundance in baseline tumor tissues was associated with resistance to anti-PD therapy in patients with NSCLC. Our study identifies a dysfunctional TIL subset, with distinct features from previously described exhausted T cells, and implies strategies to overcome immunotherapy resistance. SIGNIFICANCE: We identified a highly proliferative, overactivated, and apoptotic dysfunctional CD8+ tumor-infiltrating subpopulation that is functionally distinct from previously described exhausted T cells. This population is expanded in lung cancer tissues in a PD-1/B7-H1-dependent manner, and its abundance is associated with resistance to cancer immunotherapy, thus becoming a potential tissue biomarker.This article is highlighted in the In This Issue feature, p. 1601.
| S-EPMC9421941 | biostudies-literature
Project description:Despite the recent successes and durable responses with immune checkpoint inhibitors (ICI), many cancer patients, including those with melanoma, do not derive long-term benefits from ICI therapies. The lack of predictive biomarkers to stratify patients to targeted treatments has been the driver of primary treatment failure and represents an unmet medical need in melanoma and other cancers. Understanding genomic correlations with response and resistance to ICI will enhance cancer patients' benefits. Building on insights into interplay with the complex tumor microenvironment (TME), the ultimate goal should be assessing how the tumor 'instructs' the local immune system to create its privileged niche with a focus on genomic reprogramming within the TME. It is hypothesized that this genomic reprogramming determines the response to ICI. Furthermore, emerging genomic signatures of ICI response, including those related to neoantigens, antigen presentation, DNA repair, and oncogenic pathways, are gaining momentum. In addition, emerging data suggest a role for checkpoint regulators, T cell functionality, chromatin modifiers, and copy-number alterations in mediating the selective response to ICI. As such, efforts to contextualize genomic correlations with response into a more insightful understanding of tumor immune biology will help the development of novel biomarkers and therapeutic strategies to overcome ICI resistance.
| S-EPMC9820306 | biostudies-literature
Project description:Different mechanisms lead to immune checkpoint inhibitor (ICI) resistance. Identifying clinically useful biomarkers might improve drug selection and patients' therapy. We analyzed the soluble immune checkpoints sPD1, sPDL1, sLAG3, and sTIM3 using ELISA and their expression on circulating T cells using FACS in pre- and on-treatment blood samples of ICI treated melanoma patients. In addition, pre-treatment melanoma metastases were stained for TIM3 and LAG3 expression by IHC. Results were correlated with treatment response and progression-free survival (PFS). Resistance to anti-PD1 treatment (n = 48) was associated with high pre-treatment serum levels of sLAG3 (DCR: p = .009; PFS: p = .018; ROC cutoff >148 pg/ml) but not sPD1, sPDL1 or sTIM3. In contrast, resistance to ipilimumab plus nivolumab (n = 42) was associated with high levels of sPD1 (DCR: p = .019, PFS: p = .046; ROC cutoff >167 pg/ml) but not sPDL1, sLAG3 or sTIM3. Both treatment regimens shared a profound increase of sPD1 serum levels with treatment (p < .0001). FACS analysis revealed reduced frequencies of CD3+ CD8+ PD1 + T cells (p = .028) in anti-PD1-resistant patients, whereas increased frequencies of CD3+ CD4+ LAG3 + T cells characterized patients resistant to ipilimumab plus nivolumab (p = .033). Unlike anti-PD1 monotherapy, combination blockade significantly increased proliferating T cells (CD3+ CD8+ Ki67 + T cells; p < .0001) and eosinophils (p = .001). In melanoma metastases, an increased infiltration with TIM3+ or LAG3 + T cells in the tumor microenvironment correlated with a shorter PFS under anti-PD1 treatment (TIM3: p = .019, LAG3: p = .07). Different soluble immune checkpoints characterized checkpoint inhibitor-resistant melanoma. Measuring these serum markers may have the potential to be used in clinical routine.
| S-EPMC8158029 | biostudies-literature
Project description:BackgroundNowadays, immunotherapy targeting immune checkpoint receptors is one of the cornerstones of systemic treatment in melanoma. Homologous recombination repair (HRR) is one of the DNA damage response (DDR) pathways, which has been proved to correlate with the efficacy of platinum-based chemotherapy, PARP inhibitor therapy, and immunotherapy in a variety of cancers. However, their predictive value of HRR remained unknown in patients with advanced melanoma.MethodsData of advanced melanoma patients from an independent cohort (Samstein2018) were used to analyze the correlation with immunogenic markers and the prognostic effect of HRR on immunotherapy, and another four cohorts (pooled cohort: Miao2018, Allen 2015, Hugo2016, and Synder2014) were used for validation. Immune infiltration cell scores analyzed by TCGA-SKCM cohort were used to explore potential mechanisms related to the immune microenvironment.ResultsCompared to patients with an HRR wild type (HRRwt), those with HRR mutations (HRRmut) in anti-CTLA-4-treated patients of the Samstein2018 cohort had higher tumor mutation burden (TMB; P = 0.0041) and longer median overall survival (mOS; P = 0.0094). In terms of results validation, it was also confirmed that the mOS (P = 0.0014) of HRRmut patients receiving anti-CTLA-4 therapy was significantly better than that of HRRwt patients in the pooled cohort, and objective response rates (ORR; P = 0.0053) were also found to be significant. However, there was no significant difference in mOS between HRRmut patients who received anti-PD-1/L1 therapy and HRRwt patients in either the discovery (Samstein2018 cohort, P = 0.94) or validation (pooled cohort, P = 0.96) set. Exploratory analysis found that although HRRmut patients showed no significant difference in mOS between anti-CTLA-4 and anti-PD-1/L1 therapy (P = 0.79), the mOS value of the anti-CTLA-4 therapy group (31.7 months) in HRRmut patients was numerically superior to the anti-PD-1/L1 therapy group (27.5 months). In contrast, the mOS of the anti-CTLA-4 therapy group was significantly lower than that of the anti-PD-1/L1 therapy group (12.4 vs. 32.0 months) in HRRwt patients. In addition, transcriptome profiling analysis revealed that the 29 (65.9%)-gene mutation of the HRR pathway associated with reshaping of the immunological microenvironment in melanoma.ConclusionsHRR mutations were associated with a higher TMB level, and better anti-CTLA-4 therapy outcomes. HRR may serve as an independent predictor of anti-CTLA-4 therapy efficacy in patients with advanced melanoma and their clinical value warrants further investigation.
| S-EPMC9381822 | biostudies-literature
Project description:BACKGROUND:Clinical benefit from programmed cell death 1 receptor (PD-1) inhibitors relies on reinvigoration of endogenous antitumor immunity. Nonetheless, robust immunological markers, based on circulating immune cell subsets associated with therapeutic efficacy are yet to be validated. METHODS:We isolated peripheral blood mononuclear cell from three independent cohorts of melanoma and Merkel cell carcinoma patients treated with PD-1 inhibitor, at baseline and longitudinally after therapy. Using multiparameter flow cytometry and cell sorting, we isolated four subsets of CD8+ T cells, based on PD-1 and TIGIT expression profiles. We performed phenotypic characterization, T cell receptor sequencing, targeted transcriptomic analysis and antitumor reactivity assays to thoroughly characterize each of these subsets. RESULTS:We documented that the frequency of circulating PD-1+TIGIT+ (DPOS) CD8+ T-cells after 1?month of anti-PD-1 therapy was associated with clinical response and overall survival. This DPOS T-cell population was enriched in highly activated T-cells, tumor-specific and emerging T-cell clonotypes and T lymphocytes overexpressing CXCR5, a key marker of the CD8 cytotoxic follicular T cell population. Additionally, transcriptomic profiling defined a specific gene signature for this population as well as the overexpression of specific pathways associated with the therapeutic response. CONCLUSIONS:Our results provide a convincing rationale for monitoring this PD-1+TIGIT+ circulating population as an early cellular-based marker of therapeutic response to anti-PD-1 therapy.
| S-EPMC7668369 | biostudies-literature
Project description:The nature and role of global transcriptional deregulations in cancers are not fully understood. We report that a large proportion of cancers have widespread defects in mRNA transcription elongation (TE). Cancers with TE defects (TEdeff) display spurious transcription and defective mRNA processing of genes characterized by long genomic length, poised promoters and inducible expression. Signaling pathways regulated by such genes, such as pro-inflammatory response pathways, are consistently suppressed in TEdeff tumors. Remarkably, TEdeff correlates with the poor response and outcome in immunotherapy, but not chemo- or targeted therapy, -treated renal cell carcinoma and metastatic melanoma patients. Forced pharmacologic or genetic induction of TEdeff in tumor cells impairs pro-inflammatory response signaling, and imposes resistance to the innate and adaptive anti-tumor immune responses and checkpoint inhibitor therapy in vivo. Therefore, defective TE is a previously unknown mechanism of tumor immune resistance, and should be assessed in cancer patients undergoing immunotherapy.
| S-EPMC6199328 | biostudies-literature