Systemic CD4 Immunity as a Key Contributor to PD-L1/PD-1 Blockade Immunotherapy Efficacy

Zuazo, Miren; Arasanz, Hugo; Bocanegra, Ana; Fernández, Gonzalo; Chocarro, Luisa; Vera, Ruth; Kochan, Grazyna; Escors, David

doi:10.3389/fimmu.2020.586907

Cited by 51 publications

(41 citation statements)

References 96 publications

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“…Both pathways were identified (CTLA4 Signaling in Cytotoxic T Lymphocytes and PD-1, PD-L1 cancer immunotherapy pathway), as additional validation for this screening. Consistent with identification of the CD4-LCK-MEC2C axis, CD4 was identified as a key contributor to the PD1/PD-L1 immunotherapy efficacy, showing a critical role of CD4-mediated pathway in antagonizing cancer [ 40 ].…”

Section: Discussionmentioning

confidence: 66%

Survival-Critical Genes Associated with Copy Number Alterations in Lung Adenocarcinoma

Rao

Farooqui

et al. 2021

Cancers

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Chromosome Instability (CIN) in tumors affects carcinogenesis, drug resistance, and recurrence/prognosis. Thus, it has a high impact on outcomes in clinic. However, how CIN occurs in human tumors remains elusive. Although cells with CIN (i.e., pre/early cancer cells) are proposed to be removed by apoptosis and/or a surveillance mechanism, this surveillance mechanism is poorly understood. Here we employed a novel data-mining strategy (Gene Expression to Copy Number Alterations [CNA]; “GE-CNA”) to comprehensively identify 1578 genes that associate with CIN, indicated by genomic CNA as its surrogate marker, in human lung adenocarcinoma. We found that (a) amplification/insertion CNA is facilitated by over-expressions of DNA replication stressor and suppressed by a broad range of immune cells (T-, B-, NK-cells, leukocytes), and (b) deletion CNA is facilitated by over-expressions of mitotic regulator genes and suppressed predominantly by leukocytes guided by leukocyte extravasation signaling. Among the 39 CNA- and survival-associated genes, the purine metabolism (PPAT, PAICS), immune-regulating CD4-LCK-MEC2C and CCL14-CCR1 axes, and ALOX5 emerged as survival-critical pathways. These findings revealed a broad role of the immune system in suppressing CIN/CNA and cancer development in lung, and identified components representing potential targets for future chemotherapy, chemoprevention, and immunomodulation approaches for lung adenocarcinoma.

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Section: Discussionmentioning

confidence: 66%

Survival-Critical Genes Associated with Copy Number Alterations in Lung Adenocarcinoma

Rao

Farooqui

et al. 2021

Cancers

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“…Some examples are PD-1, CD244, CD160, TIM-3, CTLA-4, and LAG-3 [ 117 ]. Particularly, ICIs blocking PD-1/PD-L1 interactions have revolutionized oncology, with very promising results for cancer treatment [ 118 , 119 , 120 , 121 ]. Due to the efficacy of these ICIs, a set of second-generation ICIs such as anti-LAG-3 antibodies and combinations are being evaluated at the preclinical and clinical levels [ 7 ].…”

Section: Clinical Landscape Of Lag-3-targeted Therapymentioning

confidence: 99%

Understanding LAG-3 Signaling

Chocarro

Blanco

Zuazo

et al. 2021

IJMS

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115

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Lymphocyte activation gene 3 (LAG-3) is a cell surface inhibitory receptor with multiple biological activities over T cell activation and effector functions. LAG-3 plays a regulatory role in immunity and emerged some time ago as an inhibitory immune checkpoint molecule comparable to PD-1 and CTLA-4 and a potential target for enhancing anti-cancer immune responses. LAG-3 is the third inhibitory receptor to be exploited in human anti-cancer immunotherapies, and it is considered a potential next-generation cancer immunotherapy target in human therapy, right next to PD-1 and CTLA-4. Unlike PD-1 and CTLA-4, the exact mechanisms of action of LAG-3 and its relationship with other immune checkpoint molecules remain poorly understood. This is partly caused by the presence of non-conventional signaling motifs in its intracellular domain that are different from other conventional immunoregulatory signaling motifs but with similar inhibitory activities. Here we summarize the current understanding of LAG-3 signaling and its role in LAG-3 functions, from its mechanisms of action to clinical applications.

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“…Multiple studies have indicated that CD4 T cells mediate antitumor effects through mechanisms that vary according to tumor microenvironments ( Ngiow and Young, 2020 ). In some settings, CD4 T cells became cytotoxic in the presence of IL-2, or in the absence of regulatory T cells ( Zuazo et al., 2020 ). More recent studies have indicated that cytotoxic CD4 T cells reach up to 25% of all tumor-infiltrating lymphocytes, supporting an essential role which contributes toward better survival ( Maibach et al., 2020 ).…”

Section: Discussionmentioning

confidence: 99%

PD-1-stimulated T cell subsets are transcriptionally and functionally distinct

et al. 2021

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Summary Despite the obvious inhibitory outcome of PD-1 signaling, an additional series of functions are activated. We have observed that T cells stimulated through the T cell receptor (TCR) and PD-1 primarily do not proliferate; however, there is a population of cells that proliferates more than through TCR stimulation alone. In this study, we performed flow cytometry and RNA sequencing on individual populations of T cells and discovered that unlike naive T cells, which were inhibited following PD-1 ligation, T cells that proliferated more following PD-1 ligation were associated with effector and central memory phenotypes. We showed that these populations had different gene expression profiles following PD-1 ligation with PD-L1 compared to PD-L2. The presence of transcriptionally and functionally distinct T cell populations responsive to PD-1 ligation provides new insights into the biology of PD-1 and suggest the use of T cell subset-specific approaches to improve the clinical outcome of PD-1 blockade.

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Systemic CD4 Immunity as a Key Contributor to PD-L1/PD-1 Blockade Immunotherapy Efficacy

Cited by 51 publications

References 96 publications

Survival-Critical Genes Associated with Copy Number Alterations in Lung Adenocarcinoma

Survival-Critical Genes Associated with Copy Number Alterations in Lung Adenocarcinoma

Understanding LAG-3 Signaling

PD-1-stimulated T cell subsets are transcriptionally and functionally distinct

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