Dysfunctional CD8 T Cells Form a Proliferative, Dynamically Regulated Compartment within Human Melanoma

Li, Hanjie; Leun, Anne M. van der; Yofe, Ido; Lubling, Yaniv; Gelbard-Solodkin, Dikla; Akkooi, Alexander C. J. van; Braber, Marlous van den; Rozeman, Elisa A.; Haanen, John B.A.G.; Blank, Christian U.; Horlings, Hugo M.; David, Eyal; Baran, Yael; Bercovich, Akhiad; Lifshitz, Aviezer; Schumacher, Ton N.; Tanay, Amos; Amit, Ido

doi:10.1016/j.cell.2018.11.043

Cited by 819 publications

(874 citation statements)

References 36 publications

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“…We identified about 25% of total immune cells infiltrating BCs as CD14 + TAMs that express variable levels of CD163, underlying the phenotypic heterogeneity in TAMs. Through high‐dimensional analysis approaches, several recent reports have uncovered TAM heterogeneity at the single‐cell level in distinct tumor types, including BC, clear cell renal cell carcinoma, melanoma and lung adenocarcinoma . These studies revealed a great variety of distinct phenotypic TAM subsets that co‐exist by sharing the expression of well‐established M1 and M2 markers.…”

Section: Discussionmentioning

confidence: 99%

CD163⁺ tumor‐associated macrophage accumulation in breast cancer patients reflects both local differentiation signals and systemic skewing of monocytes

et al. 2020

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Objectives The accumulation of tumor‐associated macrophages (TAMs) is correlated with poor clinical outcome, but the mechanisms governing their differentiation from circulating monocytes remain unclear in humans. Methods Using multicolor flow cytometry, we evaluated TAMs phenotype in 93 breast cancer (BC) patients. Furthermore, monocytes from healthy donors were cultured in the presence of supernatants from dilacerated primary tumors to investigate their differentiation into macrophages (MΦ) in vitro. Additionally, we used transcriptomic analysis to evaluate BC patients’ blood monocytes profiles. Results We observed that high intra‐tumor CD163‐expressing TAM density is predictive of reduced survival in BC patients. In vitro, M‐CSF, TGF‐β and VEGF from primary tumor supernatants skewed the differentiation of healthy donor blood monocytes towards CD163highCD86lowIL‐10high M2‐like MΦ that strongly suppressed CD4+ T‐cell expansion via PD‐L1 and IL‐10. In addition, blood monocytes from about 40% of BC patients displayed an altered response to in vitro stimulation, being refractory to type‐1 MΦ (M1‐MΦ) differentiation and secreting higher amounts of immunosuppressive, metastatic‐related and angiogenic cytokines. Aside from showing that monocyte transcriptome is significantly altered by the presence of BC, we also demonstrated an overall metabolic de‐activation in refractory monocytes of BC patients. In contrast, monocytes from sensitive BC patients undergoing normal M1‐MΦ differentiation showed up‐regulation of IFN‐response genes and had no signs of metabolic alteration. Conclusion Altogether, our results suggest that systemic factors skew BC patient blood monocytes towards a pro‐metastatic profile, resulting in the accumulation of further polarised CD163high TAMs resembling type‐2 MΦ (M2‐MΦ) in the local BC microenvironment. These data indicate that monitoring circulating monocytes in BC patients may provide an indication of early systemic alterations induced by cancer and, thus, be instrumental in the development of improved personalised immunotherapeutic interventions.

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Section: Discussionmentioning

confidence: 99%

CD163⁺ tumor‐associated macrophage accumulation in breast cancer patients reflects both local differentiation signals and systemic skewing of monocytes

et al. 2020

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“…(23,25,26,40,41) Indeed, recent single-cell transcriptomic analyses indicate that a proportion of CD8 + TILs that were previously identified as exhausted are indeed highly proliferating and undergoing a dynamic differentiation process. (42,43) This highlights the importance of distinguishing the subset of exhausted T cells in a viable T-cell activation state. Compared to PD-1 int and 4-1BB neg PD-1 high CD8 + TILs, we found that 4-1BB pos PD-1 high CD8 + TILs showed the highest levels of T-cell activation markers and TCRresponsive transcription factors as well as significant enrichment for T-cell-activation-related gene signatures.…”

Section: Discussionmentioning

confidence: 99%

4‐1BB Delineates Distinct Activation Status of Exhausted Tumor‐Infiltrating CD8+ T Cells in Hepatocellular Carcinoma

et al. 2019

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Background and Aims Targeting costimulatory receptors with agonistic antibodies is a promising cancer immunotherapy option. We aimed to investigate costimulatory receptor expression, particularly 4‐1BB (CD137 or tumor necrosis factor receptor superfamily member 9), on tumor‐infiltrating CD8+ T cells (CD8+ tumor‐infiltrating lymphocytes [TILs]) and its association with distinct T‐cell activation features among exhausted CD8+ TILs in hepatocellular carcinoma (HCC). Approach and Results Tumor tissues, adjacent nontumor tissues, and peripheral blood were collected from HCC patients undergoing surgical resection (n = 79). Lymphocytes were isolated and used for multicolor flow cytometry, RNA‐sequencing, and in vitro functional restoration assays. Among the examined costimulatory receptors, 4‐1BB was most prominently expressed on CD8+ TILs. 4‐1BB expression was almost exclusively detected on CD8+ T cells in the tumor—especially on programmed death 1 (PD‐1)high cells and not PD‐1int and PD‐1neg cells. Compared to PD‐1int and 4‐1BBnegPD‐1high CD8+ TILs, 4‐1BBposPD‐1high CD8+ TILs exhibited higher levels of tumor reactivity and T‐cell activation markers and significant enrichment for T‐cell activation gene signatures. Per‐patient analysis revealed positive correlations between percentages of 4‐1BBpos cells among CD8+ TILs and levels of parameters of tumor reactivity and T‐cell activation. Among highly exhausted PD‐1high CD8+ TILs, 4‐1BBpos cells harbored higher proportions of cells with proliferative and reinvigoration potential. Our 4‐1BB–related gene signature predicted survival outcomes of HCC patients in the The Cancer Genome Atlas cohort. 4‐1BB agonistic antibodies enhanced the function of CD8+ TILs and further enhanced the anti‐PD‐1–mediated reinvigoration of CD8+ TILs, especially in cases showing high levels of T‐cell activation. Conclusion 4‐1BB expression on CD8+ TILs represents a distinct activation state among highly exhausted CD8+ T cells in HCC. 4‐1BB costimulation with agonistic antibodies may be a promising strategy for treating HCCs exhibiting prominent T‐cell activation.

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“…The mean expression level of PD‐1 and PD‐1 T‐cell frequency strongly correlated with CD4+ and CD8+ subsets, indicating that these cells originated from T‐cell expansion (Fig. e ) . Analysis of PD‐1+ cluster frequencies based on tumor grade showed that the samples of early‐stage (Stage II) had similar levels of PD‐1+ T cells as compared to the samples of advanced stages (Stages III and IV, Supporting Information Fig.…”

Section: Resultsmentioning

confidence: 83%

Phenotype molding of T cells in colorectal cancer by single‐cell analysis

Liu

Fan

et al. 2020

Intl Journal of Cancer

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The majority of patients with microsatellite stable (MSS) colorectal cancer (CRC) do not benefit from the immunotherapies directed at rescuing T‐cell functions. Therefore, complete understanding of T‐cell phenotypes and functional status in the CRC microenvironment is desirable. Here, we applied single‐cell mass cytometry to mold the T‐cell phenotype in 18 patients with MSS CRC for better understanding of CRC as a systemic disease and to search for tumor‐driven T‐cell profile changes. We show interpatient and intrapatient phenotypic diversity of T‐cell subsets. We revealed increased immunosuppressive/exhausted T‐cell phenotypes at tumor lesions. CD8+ CD28− immunosenescent T cells with impaired proliferation capacity dominate the T‐cell compartment. As per the transcriptome and quantitative real time‐PCR analysis, the accumulation of immunosuppressive cells is driven by the tumor microenvironment. T‐cell profiles are similar between patients at early and late stages, indicating that the immunosuppressive microenvironment is formulated early during CRC development. Mapping of T‐cell infiltration and understanding of the mechanisms underlying their regulation may provide valuable information to boost the immune response in patients with MSS CRC.

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Dysfunctional CD8 T Cells Form a Proliferative, Dynamically Regulated Compartment within Human Melanoma

Cited by 819 publications

References 36 publications

CD163⁺ tumor‐associated macrophage accumulation in breast cancer patients reflects both local differentiation signals and systemic skewing of monocytes

CD163⁺ tumor‐associated macrophage accumulation in breast cancer patients reflects both local differentiation signals and systemic skewing of monocytes

4‐1BB Delineates Distinct Activation Status of Exhausted Tumor‐Infiltrating CD8+ T Cells in Hepatocellular Carcinoma

Phenotype molding of T cells in colorectal cancer by single‐cell analysis

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Dysfunctional CD8 T Cells Form a Proliferative, Dynamically Regulated Compartment within Human Melanoma

Cited by 819 publications

References 36 publications

CD163+ tumor‐associated macrophage accumulation in breast cancer patients reflects both local differentiation signals and systemic skewing of monocytes

CD163+ tumor‐associated macrophage accumulation in breast cancer patients reflects both local differentiation signals and systemic skewing of monocytes

4‐1BB Delineates Distinct Activation Status of Exhausted Tumor‐Infiltrating CD8+ T Cells in Hepatocellular Carcinoma

Phenotype molding of T cells in colorectal cancer by single‐cell analysis

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CD163⁺ tumor‐associated macrophage accumulation in breast cancer patients reflects both local differentiation signals and systemic skewing of monocytes

CD163⁺ tumor‐associated macrophage accumulation in breast cancer patients reflects both local differentiation signals and systemic skewing of monocytes