A Burned-Out CD8+ T-cell Subset Expands in the Tumor Microenvironment and Curbs Cancer Immunotherapy

Sanmamed, Miguel F.; Nie, Xinxin; Desai, Shruti; Villaroel-Espíndola, Franz; Badri, Ti; Zhao, Dejian; Kim, Anthony W.; Lan, Jing; Zhang, Tianxiang; Quinlan, Edward; Cheng, Xiaoxiao; Han, Xue; Vesely, Matthew D.; Nassar, Ala F.; Sun, Jingwei; Zhang, Yu; Kim, Tae Kon; Wang, Jun; Melero, Ignacio; Herbst, Roy S.; Schalper, Kurt A.; Chen, Lieping

doi:10.1158/2159-8290.cd-20-0962

Cited by 101 publications

(84 citation statements)

References 48 publications

(26 reference statements)

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“…The enhanced activity of CD8 + T cells was also associated with a reduction in the expression of TIM3 (T-cell immunoglobulin domain and mucin domain 3) and PD-1, which are markers of dysfunction and exhaustion of CD8 + T cells (Supplementary Fig. S2F) (32)(33)(34).…”

Section: Resultsmentioning

confidence: 97%

MEK1/2 inhibition transiently alters the tumor immune microenvironment to enhance immunotherapy efficacy against head and neck cancer

Prasad

Zorea

Jagadeeshan

et al. 2021

Preprint

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Although the mitogen-activated protein kinases (MAPK) pathway is hyperactive in head and neck cancer (HNC), inhibition of MEK1/2 in HNC patients has not shown clinically meaningful activity. Using pre-clinical HNC models, we demonstrated that treatment with the MEK1/2 blocker trametinib delays HNC initiation and progression by reducing tumor cell proliferation and enhancing the anti-tumor immunity of CD8+ T cells. Further activation of CD8+ T cells by supplementation with anti-programmed death-1 (αPD-1) antibody eliminated tumors and induced an immune memory in the cured mice. Mechanistically, an early response to trametinib treatment sensitized tumors to αPD-1-supplementation by attenuating the expression of tumor-derived colony-stimulating factor-1 (CSF-1), which reduced the abundance of two CSF-1R+CD11c+ myeloid-derived suppressor cell (MDSC) populations in the tumor microenvironment (TME). In contrast, prolonged treatment with trametinib abolished the anti-tumor activity of αPD-1, because tumor cells undergoing the epithelial to mesenchymal transition (EMT) in response to trametinib restored CSF-1 expression and re-created an immune-suppressive TME. These findings provide the rationale for testing the trametinib/αPD-1 combination in HNC and highlight the importance of sensitizing tumors to immunotherapies by using targeted therapies to interfere with the host-tumor interaction. Graphical abstract

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Section: Resultsmentioning

confidence: 97%

MEK1/2 inhibition transiently alters the tumor immune microenvironment to enhance immunotherapy efficacy against head and neck cancer

Prasad

Zorea

Jagadeeshan

et al. 2021

Preprint

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“…Meanwhile, confronting immune attack caused by TILs, tumor cells could upregulate the expression of immune checkpoint genes with the purpose of inhibiting T cell activity resulting in immune escape, which also explains the consistent correlation between LOXL3 and immune checkpoint genes. This mechanism mentioned above is known as "adaptive immune resistance" [36] .…”

Section: Discussionmentioning

confidence: 99%

Identification of LOXL3-associating immune infiltration landscape and prognostic value in hepatocellular carcinoma

et al. 2021

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Hepatocellular carcinoma (HCC), the most common type of hepatic malignancies, remains a global health challenge with multiple aetiologies and low ve-year survival rate. In recent years, breakthroughs in the eld of tumor immunotherapy with immune checkpoint inhibitors (ICIs) have made a therapeutic revolution, which has been shown to improve the prognosis of patients with HCC. Immune in ltrates represent a major component of tumor microenvironment (TME), and play an essential role in both tumor progression and therapeutic response. The major unmet challenge in tumor immunotherapy is exploring the intrinsic and extrinsic mechanisms of TME promoting the management of HCC. Lysyl oxidase like 3 (LOXL3) participates in the remodeling of extracellular matrix (ECM) and the cross-linking of collagen and elastic bers. It has been reported that LOXL3 is associated with the development and tumorigenesis of multiple types of cancer. In this study, we rst found that LOXL3 gene was upregulated in tumor tissues compared with the normal tissues. Furthermore, LOXL3 expression is positively correlated with the in ltration of multiple immune cells and the expression of immune checkpoint genes in HCC. Meanwhile, high LOXL3 expression predicted poor outcomes of the patients with HCC. Functional enrichment analysis suggested that LOXL3 was mainly linked to extracellular structure and matrix organization, cell−cell adhesion, and T cell activation. This is the rst comprehensive study to indicate that LOXL3 is correlated with immune in ltrates and may serve as a novel biomarker predicting prognosis and immunotherapy in HCC.

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“…Thus, ICI therapies targeting PD-1 typically induce IFNγ through reinvigoration of T cells and activation NK cells. Recent discovery of a distinct dysregulated CD8 + TIL population in the TME that demonstrated higher levels of activation, proliferation and apoptosis with decreased IFNγ production appeared to expand through tumourigenesis and associated with advanced clinical stage and promoted ICI resistance in both clinical and pre-clinical samples 56 .…”

Section: Discussionmentioning

confidence: 99%

IL-2 stromal signatures dissect immunotherapy response groups in non-small cell lung cancer (NSCLC)

Monkman

Kim

Mayer

et al. 2021

Preprint

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IntroductionImmunotherapies, such as immune checkpoint inhibitors (ICI) have shown durable benefit in a subset of non-small cell lung cancer (NSCLC) patients. The mechanisms for this are not fully understood, however the composition and activation status of the cellular milieu contained within the tumour microenvironment (TME) is becomingly increasingly recognised as a driving factor in treatment-refractory disease.MethodsHere, we employed multiplex IHC (mIHC), and digital spatial profiling (DSP) to capture the targeted immune proteome and transcriptome of tumour and TME compartments of pre-treatment samples from a 2nd line NSCLC ICI-treated cohort (n=41 patients; n=25 responders, n=16 non-responders).ResultsWe demonstrate by mIHC that the interaction of CD68+ macrophages with PD1+, FoxP3+ cells is significantly enriched in ICI refractory tumours (p=0.012). Our study revealed that patients sensitive to ICI therapy expressed higher levels of IL2 receptor alpha (CD25, p=0.028) within the tumour compartments, which corresponded with the increased expression of IL2 mRNA (p=0.001) within their stroma, indicative of key conditions for ICI efficacy prior to treatment. IL2 mRNA levels within the stroma positively correlated with the expression of pro-apoptotic markers cleaved caspase 9 (p=2e-5) and BAD (p=5.5e-4) and negatively correlated with levels of memory T cells (CD45RO) (p=7e-4). Immuno-inhibitory markers CTLA-4 (p=0.021) and IDO-1 (p=0.023) were also supressed in ICI-responsive patients. Of note, tumour CD44 (p=0.02) was depleted in the response group and corresponded inversely with significantly higher stromal expression of its ligand SPP1 (osteopontin, p=0.008). Analysis of differentially expressed transcripts indicated the potential inhibition of stromal interferon-gamma (IFNγ) activity, as well as estrogen-receptor and Wnt-1 signalling activity within the tumour cells of ICI responsive patients. Cox survival analysis indicated tumour CD44 expression was associated with poorer prognosis (HR=1.61, p=0.01), consistent with its depletion in ICI sensitive patients. Similarly, stromal CTLA-4 (HR=1.78, p=0.003) and MDSC/M2 macrophage marker ARG1 (HR=2.37, p=0.01) were associated with poorer outcome while levels of apoptotic marker BAD (HR=0.5, p=0.01) appeared protective. Interestingly, stromal mRNA for E-selectin (HR=652, p=0.001), CCL17 (HR=70, p=0.006) and MTOR (HR=1065, p=0.008) were highly associated with poorer outcome, indicating pro-tumourigenic features in the tumour microenvironment that may facilitate ICI resistance.ConclusionsThrough multi-modal approaches, we have dissected the characteristics of NSCLC and provide evidence for the role of IL2 and stromal activation by osteopontin in the efficacy of current generations of ICI therapy. The enrichment of SPP1 in the stroma of ICI sensitive patients in our data is a novel finding, indicative of stromal activation that may aid immune cell survival and activity despite no clear association with increased levels of immune infiltrate.

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A Burned-Out CD8+ T-cell Subset Expands in the Tumor Microenvironment and Curbs Cancer Immunotherapy

Cited by 101 publications

References 48 publications

MEK1/2 inhibition transiently alters the tumor immune microenvironment to enhance immunotherapy efficacy against head and neck cancer

MEK1/2 inhibition transiently alters the tumor immune microenvironment to enhance immunotherapy efficacy against head and neck cancer

Identification of LOXL3-associating immune infiltration landscape and prognostic value in hepatocellular carcinoma

IL-2 stromal signatures dissect immunotherapy response groups in non-small cell lung cancer (NSCLC)

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