Spatial and Temporal Changes in PD-L1 Expression in Cancer: The Role of Genetic Drivers, Tumor Microenvironment and Resistance to Therapy

Shklovskaya, Elena; Rizos, Helen

doi:10.3390/ijms21197139

Cited by 36 publications

(30 citation statements)

References 180 publications

(260 reference statements)

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“…Although some studies suggest that PD-L1 expression is a negative prognostic factor, this is mainly due to the assessment of expression in tumor cells [ 33 , 58 , 59 ] and tumor staging. The contradictory results from the metastatic setting and from the early-stages [ 60 ] are probably due to temporal and spatial differences in the microenvironment and PD-L1 expression [ 61 , 62 , 63 , 64 ].…”

Section: Discussionmentioning

confidence: 99%

“…With respect to survival, patients in the CMS1 group, defined by dMMR, have the best prognosis in early-stage CRC [ 2 , 29 , 67 , 68 ] independent of the degree of PD-L1 expression. Further, the value of PD-L1 expression as an immunohistochemical biomarker of good prognosis when assessed in immune cells has been suggested by several studies and meta-analyses [ 33 , 47 , 63 , 69 ]. It is independent of MMR status [ 28 , 29 , 67 , 70 , 71 ].…”

Section: Discussionmentioning

confidence: 99%

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PD-L1 as a Prognostic Factor in Early-Stage Colon Carcinoma within the Immunohistochemical Molecular Subtype Classification

Azcue

Encı́o

Setas

et al. 2021

Cancers

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Background. There is a patent need to better characterize early-stage colorectal cancer (CRC) patients. PD-1 ligand (PD-L1) expression has been proposed as a prognostic factor but yields mixed results in different settings. The Consensus Molecular Subtype (CMS) classification has yet to be integrated into clinical practice. We sought to evaluate the prognostic value of PD-L1 expression overall and within CMS in early-stage colon cancer patients, in the hope of assisting treatment choice in this setting. Methods. Tissue-microarrays were constructed from tumor samples of 162 stage II/III CRC patients. They underwent automatic immunohistochemical staining for PD-L1 and the proposed CMS panel. Primary endpoints were overall survival (OS) and disease-free survival (DFS). Results. PD-L1 expression was significantly and independently associated with better prognosis (HR = 0.46 (0.26–0.82), p = 0.009) and was mostly seen in immune cells of the tumor-related stroma. CMS4 five-folds the risk of mortalitycompared with CMS1 (HR = 5.58 (1.36, 22.0), p = 0.034). In the subgroup CMS2/CMS3 analysis, PD-L1 expression significantly differentiated individuals with better OS (p = 0.004) and DFS (p < 0.001). Conclusions. Our study suggests that PD-L1 expression is an independent prognostic factor in patients with stage II/III colon cancer. Additionally, it successfully differentiates patients with better prognosis in the CMS2/CMS3 group and may prove significant for the clinical relevance of the CMS classification.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

PD-L1 as a Prognostic Factor in Early-Stage Colon Carcinoma within the Immunohistochemical Molecular Subtype Classification

Azcue

Encı́o

Setas

et al. 2021

Cancers

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“…The rationale here is to re-direct the response towards CD4 T cells (with the use of anti-CTLA-4 helping attenuate Treg-mediated suppression), plus NK-targeting drugs (ICB or antibodies preventing NKG2DL shedding) to prevent hematogenic metastatic spread [281,282]. In this setting, therapeutic blockade of PD-L1 will help unleash the reactivity of PD-L1-expressing NK cells against MHC-I low tumors [290], while also improving antigen presentation in the tumor microenvironment [347]. This approach described in this section is suitable for tumors amenable to quantitative flow cytometry as described in [34].…”

Section: Discussionmentioning

confidence: 99%

MHC Class I Deficiency in Solid Tumors and Therapeutic Strategies to Overcome It

Shklovskaya

Rizos

2021

IJMS

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It is now well accepted that the immune system can control cancer growth. However, tumors escape immune-mediated control through multiple mechanisms and the downregulation or loss of major histocompatibility class (MHC)-I molecules is a common immune escape mechanism in many cancers. MHC-I molecules present antigenic peptides to cytotoxic T cells, and MHC-I loss can render tumor cells invisible to the immune system. In this review, we examine the dysregulation of MHC-I expression in cancer, explore the nature of MHC-I-bound antigenic peptides recognized by immune cells, and discuss therapeutic strategies that can be used to overcome MHC-I deficiency in solid tumors, with a focus on the role of natural killer (NK) cells and CD4 T cells.

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“…Tumor-associated dendritic cells (DCs) upregulate PD-L1 in response to T-cell derived inflammatory cytokines like IFN-γ [ 80 ], while M1 macrophages do so in response to another inflammatory cytokine, interleukin (IL)-1β [ 81 ]. PD-L1 + DCs can lead to functional inactivation of T cells upon interaction with PD-1 [ 82 ]. Similarly, other PD-L1 + antigen-presenting cells like macrophages can induce anergy in T cells upon interaction with PD-1 [ 83 ], explaining why expression of PD-L1 on immune cells, rather than tumor cells, has been found in some studies to correlate with a favorable response to anti-PD-1 therapy [ 84 ].…”

Section: Why Non-depleting Antibodies Have Been Used Against Inhibitory Icpmlsmentioning

confidence: 99%

Depleting Tumor Cells Expressing Immune Checkpoint Ligands—A New Approach to Combat Cancer

Marcucci

Rumio

2021

Cells

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Antibodies against inhibitory immune checkpoint molecules (ICPMs), referred to as immune checkpoint inhibitors (ICIs), have gained a prominent place in cancer therapy. Several ICIs in clinical use have been engineered to be devoid of effector functions because of the fear that ICIs with preserved effector functions could deplete immune cells, thereby curtailing antitumor immune responses. ICPM ligands (ICPMLs), however, are often overexpressed on a sizeable fraction of tumor cells of many tumor types and these tumor cells display an aggressive phenotype with changes typical of tumor cells undergoing an epithelial-mesenchymal transition. Moreover, immune cells expressing ICPMLs are often endowed with immunosuppressive or immune-deviated functionalities. Taken together, these observations suggest that compounds with the potential of depleting cells expressing ICPMLs may become useful tools for tumor therapy. In this article, we summarize the current state of the art of these compounds, including avelumab, which is the only ICI targeting an ICPML with preserved effector functions that has gained approval so far. We also discuss approaches allowing to obtain compounds with enhanced tumor cell-depleting potential compared to native antibodies. Eventually, we propose treatment protocols that may be applied in order to optimize the therapeutic efficacy of compounds that deplete cells expressing ICPMLs.

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Spatial and Temporal Changes in PD-L1 Expression in Cancer: The Role of Genetic Drivers, Tumor Microenvironment and Resistance to Therapy

Cited by 36 publications

References 180 publications

PD-L1 as a Prognostic Factor in Early-Stage Colon Carcinoma within the Immunohistochemical Molecular Subtype Classification

PD-L1 as a Prognostic Factor in Early-Stage Colon Carcinoma within the Immunohistochemical Molecular Subtype Classification

MHC Class I Deficiency in Solid Tumors and Therapeutic Strategies to Overcome It

Depleting Tumor Cells Expressing Immune Checkpoint Ligands—A New Approach to Combat Cancer

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