Expression of programmed death-ligand 1 (PD-L1) is frequently observed in human cancers. Binding of PD-L1 to its receptor PD-1 on activated T cells inhibits anti-tumor immunity by counteracting ...T cell-activating signals. Antibody-based PD-1-PD-L1 inhibitors can induce durable tumor remissions in patients with diverse advanced cancers, and thus expression of PD-L1 on tumor cells and other cells in the tumor microenviroment is of major clinical relevance. Here we review the roles of the PD-1-PD-L1 axis in cancer, focusing on recent findings on the mechanisms that regulate PD-L1 expression at the transcriptional, posttranscriptional, and protein level. We place this knowledge in the context of observations in the clinic and discuss how it may inform the design of more precise and effective cancer immune checkpoint therapies.
Schumacher et al. review the mechanisms that control PD-L1 expression in cancer and discuss how the growing understanding of the regulation and function of the PD-1-PD-L1 axis can guide more precise and effective immune checkpoint therapies.
Tertiary lymphoid structures in cancer Schumacher, Ton N; Thommen, Daniela S
Science (American Association for the Advancement of Science),
2022-Jan-07, Volume:
375, Issue:
6576
Journal Article
Peer reviewed
Ectopic lymphoid aggregates, termed tertiary lymphoid structures (TLSs), are formed in numerous cancer types, and, with few exceptions, their presence is associated with superior prognosis and ...response to immunotherapy. In spite of their presumed importance, the triggers that lead to TLS formation in cancer tissue and the contribution of these structures to intratumoral immune responses remain incompletely understood. Here, we discuss the present knowledge on TLSs in cancer, focusing on (i) the drivers of TLS formation, (ii) the function and contribution of TLSs to the antitumor immune response, and (iii) the potential of TLSs as therapeutic targets in human cancers.
Cancer Neoantigens Schumacher, Ton N; Scheper, Wouter; Kvistborg, Pia
Annual review of immunology,
04/2019, Volume:
37, Issue:
1
Journal Article
Peer reviewed
Open access
Malignant transformation of cells depends on accumulation of DNA damage. Over the past years we have learned that the T cell-based immune system frequently responds to the neoantigens that arise as a ...consequence of this DNA damage. Furthermore, recognition of neoantigens appears an important driver of the clinical activity of both T cell checkpoint blockade and adoptive T cell therapy as cancer immunotherapies. Here we review the evidence for the relevance of cancer neoantigens in tumor control and the biological properties of these antigens. We discuss recent technological advances utilized to identify neoantigens, and the T cells that recognize them, in individual patients. Finally, we discuss strategies that can be employed to exploit cancer neoantigens in clinical interventions.
Neoantigens in cancer immunotherapy Schumacher, Ton N.; Schreiber, Robert D.
Science (American Association for the Advancement of Science),
04/2015, Volume:
348, Issue:
6230
Journal Article
Peer reviewed
Open access
The clinical relevance of T cells in the control of a diverse set of human cancers is now beyond doubt. However, the nature of the antigens that allow the immune system to distinguish cancer cells ...from noncancer cells has long remained obscure. Recent technological innovations have made it possible to dissect the immune response to patient-specific neoantigens that arise as a consequence of tumor-specific mutations, and emorging data suggest that recognition of such neoantigens is a major factor in the activity of clinical immunotherapies. These observations indicate that neoantigen load may form a biomarker in cancer immunotherapy and provide an incentive for the development of novel therapeutic approaches that selectively enhance T cell reactivity against this class of antigens.
Approximately 75% of objective responses to anti-programmed death 1 (PD-1) therapy in patients with melanoma are durable, lasting for years, but delayed relapses have been noted long after initial ...objective tumor regression despite continuous therapy. Mechanisms of immune escape in this context are unknown.
We analyzed biopsy samples from paired baseline and relapsing lesions in four patients with metastatic melanoma who had had an initial objective tumor regression in response to anti-PD-1 therapy (pembrolizumab) followed by disease progression months to years later.
Whole-exome sequencing detected clonal selection and outgrowth of the acquired resistant tumors and, in two of the four patients, revealed resistance-associated loss-of-function mutations in the genes encoding interferon-receptor-associated Janus kinase 1 (JAK1) or Janus kinase 2 (JAK2), concurrent with deletion of the wild-type allele. A truncating mutation in the gene encoding the antigen-presenting protein beta-2-microglobulin (B2M) was identified in a third patient. JAK1 and JAK2 truncating mutations resulted in a lack of response to interferon gamma, including insensitivity to its antiproliferative effects on cancer cells. The B2M truncating mutation led to loss of surface expression of major histocompatibility complex class I.
In this study, acquired resistance to PD-1 blockade immunotherapy in patients with melanoma was associated with defects in the pathways involved in interferon-receptor signaling and in antigen presentation. (Funded by the National Institutes of Health and others.).
T Cell Dysfunction in Cancer Thommen, Daniela S.; Schumacher, Ton N.
Cancer cell,
04/2018, Volume:
33, Issue:
4
Journal Article
Peer reviewed
Open access
Therapeutic reinvigoration of tumor-specific T cells has greatly improved clinical outcome in cancer. Nevertheless, many patients still do not achieve durable benefit. Recent evidence from studies in ...murine and human cancer suggest that intratumoral T cells display a broad spectrum of (dys-)functional states, shaped by the multifaceted suppressive signals that occur within the tumor microenvironment. Here we discuss the current understanding of T cell dysfunction in cancer, the value of novel technologies to dissect such dysfunction at the single cell level, and how our emerging understanding of T cell dysfunction may be utilized to develop personalized strategies to restore antitumor immunity.
Therapeutic reinvigoration of tumor-specific T cells has greatly improved clinical outcome in cancer. Nevertheless, many patients still do not achieve durable benefit. Recent evidence from studies in murine and human cancer suggest that intratumoral T cells display a broad spectrum of (dys-)functional states, shaped by the multifaceted suppressive signals that occur within the tumor microenvironment. Here we discuss the current understanding of T cell dysfunction in cancer, the value of novel technologies to dissect such dysfunction at the single cell level, and how our emerging understanding of T cell dysfunction may be utilized to develop personalized strategies to restore antitumor immunity.
The clinical benefit for patients with diverse types of metastatic cancers that has been observed upon blockade of the interaction between PD-1 and PD-L1 has highlighted the importance of this ...inhibitory axis in the suppression of tumour-specific T-cell responses. Notwithstanding the key role of PD-L1 expression by cells within the tumour micro-environment, our understanding of the regulation of the PD-L1 protein is limited. Here we identify, using a haploid genetic screen, CMTM6, a type-3 transmembrane protein of previously unknown function, as a regulator of the PD-L1 protein. Interference with CMTM6 expression results in impaired PD-L1 protein expression in all human tumour cell types tested and in primary human dendritic cells. Furthermore, through both a haploid genetic modifier screen in CMTM6-deficient cells and genetic complementation experiments, we demonstrate that this function is shared by its closest family member, CMTM4, but not by any of the other CMTM members tested. Notably, CMTM6 increases the PD-L1 protein pool without affecting PD-L1 (also known as CD274) transcription levels. Rather, we demonstrate that CMTM6 is present at the cell surface, associates with the PD-L1 protein, reduces its ubiquitination and increases PD-L1 protein half-life. Consistent with its role in PD-L1 protein regulation, CMTM6 enhances the ability of PD-L1-expressing tumour cells to inhibit T cells. Collectively, our data reveal that PD-L1 relies on CMTM6/4 to efficiently carry out its inhibitory function, and suggest potential new avenues to block this pathway.
The "cancer immunogram" Blank, Christian U.; Haanen, John B.; Ribas, Antoni ...
Science (American Association for the Advancement of Science),
05/2016, Volume:
352, Issue:
6286
Journal Article
Peer reviewed
Visualizing the state of cancer–immune system interactions may spur personalized therapy
The impact of cancer immunotherapy on clinical cancer care is growing rapidly. However, different ...immunotherapies remedy distinct problems in cancer–immune system interactions. What would be the most effective therapy for an individual patient? Here, a framework is proposed for describing the different interactions between cancer and the immune system in individual cases, with the aim to focus biomarker research and to help guide treatment choice.
CD8
tissue resident memory T cells (T
cells) are essential for immune defence against pathogens and malignancies, and the molecular processes that lead to T
cell formation are therefore of ...substantial biomedical interest. Prior work has demonstrated that signals present in the inflamed tissue micro-environment can promote the differentiation of memory precursor cells into mature T
cells, and it was therefore long assumed that T
cell formation adheres to a 'local divergence' model, in which T
cell lineage decisions are exclusively made within the tissue. However, a growing body of work provides evidence for a 'systemic divergence' model, in which circulating T cells already become preconditioned to preferentially give rise to the T
cell lineage, resulting in the generation of a pool of T
cell-poised T cells within the lymphoid compartment. Here, we review the emerging evidence that supports the existence of such a population of circulating T
cell progenitors, discuss current insights into their formation and highlight open questions in the field.
The T cell infiltrates that are formed in human cancers are a modifier of natural disease progression and also determine the probability of clinical response to cancer immunotherapies. Recent ...technological advances that allow the single-cell analysis of phenotypic and transcriptional states have revealed a vast heterogeneity of intratumoural T cell states, both within and between patients, and the observation of this heterogeneity makes it critical to understand the relationship between individual T cell states and therapy response. This Review covers our current knowledge of the T cell states that are present in human tumours and the role that different T cell populations have been hypothesized to play within the tumour microenvironment, with a particular focus on CD8
T cells. The three key models that are discussed herein are as follows: (1) the dysfunction of T cells in human cancer is associated with a change in T cell functionality rather than inactivity; (2) antigen recognition in the tumour microenvironment is an important driver of T cell dysfunctionality and the presence of dysfunctional T cells can hence be used as a proxy for the presence of a tumour-reactive T cell compartment; (3) a less dysfunctional population of tumour-reactive T cells may be required to drive a durable response to T cell immune checkpoint blockade.
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