Weekly Digests

2017

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Intentional mutagenesis: making cancer worse to make it better

December 20, 2017

Although it seems counterintuitive that shutting down DNA repair mechanisms in cancer could actually improve prognosis, that’s exactly the concept that Germano et al. present in a letter published in Nature. They propose that when mismatch repair (MMR) mechanisms are disrupted in colorectal tumors, new mutations, and thus new potential neoantigens, continually arise...

The battle of receptors: CAR vs TCR

December 13, 2017

Chimeric antigen receptor (CAR) T cells have successfully induced remission in patients with relapsed or refractory B cell malignancies, but a substantial portion of patients eventually relapse. Although CAR expansion and persistence are considered important attributes for long-term benefit, systematic evaluation of contributing factors has been complicated by reliance on xenograft models. In...

Why CSF1R inhibition doesn’t slow tumor growth - and how it could

December 6, 2017

CSF1R inhibition for the depletion of tumor-associated macrophages (TAMs) seemed like a promising therapeutic strategy, but while TAM depletion occurred as expected, antitumor efficacy has been incredibly limited. To understand why, Kumar et al., in a study published in Cancer Cell, revealed the additional immunosuppressive mechanism activated by CSF1R inhibition and exploited this...

How our genes let the tumors get away

November 29, 2017

How does the immune system sculpt the tumor genome even before the tumor adapts counteracting immune evasion mechanisms? Marty et al. hypothesized that antigenic oncogenic mutations are eliminated by the immune system in the early stages of tumorigenesis, and this process is dependent on which oncogenic peptides can be effectively presented by an...

What’s in your gut? The gut microbiome influences the efficacy of anti-PD-1 immunotherapy

November 22, 2017

Responses to immunotherapy vary due to a number of factors, and according to two recent papers published in Science, the gut microbiome is definitely one of them. Both papers indicated that diversity of bacteria and the abundance of certain types of bacteria can affect patients’ response to anti-PD-1 immunotherapy for some cancer types...

What’s keeping natural killer cells in check?

November 15, 2017

In a recent paper published in Nature, Molgora et al. demonstrated that interleukin-1 receptor 8 (IL-1R8), which is a negative regulator of the IL-1 receptor (ILR) and Toll-like receptor (TLR) pathways, acts as a checkpoint for natural killer (NK) cell maturation and function, and removing this checkpoint could affect tumorigenesis and metastasis. Although...

Treg cells are stronger dead than alive

November 8, 2017

T regulatory (Treg) cells are known for their immunosuppressive role in the tumor microenvironment, but surprisingly, their death might only make them stronger. In a paper published in Nature Immunology, Maj et al. observed that while live CD4+Foxp3+ Tregs are heavily recruited to tumors, they also undergo apoptosis in the tumor microenvironment (TME)...

PD-1 inhibition: it’s not just for antibodies anymore

November 1, 2017

As anti-PD-1 antibody therapy can be costly and carries a risk of an autoimmune reaction, Taylor et al. explored the possibility of using a glycogen synthase kinase GSK-3 inhibitor (GSK-3i) as a small molecule inhibitor to downregulate PD-1 in the treatment of cancer. In a recently published paper in Cancer Research, the team...

What’s happening under the hood: The cellular kinetics of a CAR T cell therapy

October 25, 2017

Therapies in which T cells are engineered to express a chimeric antigen receptor (CAR) have proven to be incredibly effective against certain hematological malignancies. In recent months, two CAR T cell therapies have earned FDA approval, and it is likely this groundbreaking strategy will continue to expand. In an effort to understand the...

Form follows function: How dendritic cell distribution within lymph nodes affects T cell response

October 18, 2017

Form follows function, and the fascinating structural microanatomy and related immunological functioning of lymph nodes revealed by Gerner et al. in The Journal of Experimental Medicine highlight their importance for rational vaccine design. Dendritic cells (DCs) within the lymphatic tissues are the key initiators of adaptive immune responses during immunization or in the...

AACR Tumor Immunology and Immunotherapy Conference

October 11, 2017

Last week, the ACIR team attended the AACR Tumor Immunology and Immunotherapy conference in Boston, MA. This week’s extensive special feature covers select sessions from the conference. Opening Keynote and Special Lecture Levi Garraway from Eli Lilly and Company opened the conference with an overview of the cancer-immunity cycle and how it relates...

Combination central tolerance and peripheral checkpoint blockade unleashes antimelanoma immunity

October 4, 2017

Central tolerance is essential for protection against autoimmune reactions, but cancers being so similar to “self”, this protective mechanism sometimes limits the immune system’s ability to fight off cancerous cells. Autoimmune regulator (Aire) is a regulator of central tolerance that is expressed predominantly in medullary thymic epithelial cells (mTECs) in the thymus. The...

Enhancing CD8+ T Cell Fatty Acid Catabolism within a Metabolically Challenging Tumor Microenvironment Increases the Efficacy of Melanoma Immunotherapy

September 27, 2017

We know that when oxygen is lacking, T cells increase their glucose uptake and glycolysis, and when glucose is lacking, cells switch to oxidative phosphorylation (OXPHOS), which can utilize many substrates for fuel, but requires oxygen. But what happens to the T cells in the tumor microenvironment (TME), which is often hypoxic and...

The inhibitory signaling receptor protocadherin-18 regulates tumor-infiltrating CD8+ T cell function

September 20, 2017

The activation of T cells from a memory to an effector state depends on the integration of the positive signal from the T cell receptor upon binding with a cognate antigen and the negative signals from any of several inhibitory signaling receptors (ISRs) binding their cognate ligands on the antigenic cell’s surface. ISRs...

The Effect of Timing is Crucial in PD-1 Blockade/Agonist-OX40 Combination Immunotherapy

September 13, 2017

Timing is everything, especially when it comes to combination immunotherapy. This was the conclusion reached by two separate research groups that evaluated the combination of agonist-OX40 and anti-PD-1 antibody therapies in different mouse models. The researchers were inspired by the challenges of optimally combining immunotherapies in the clinical setting. To address this problem...

PDL1 Signals through Conserved Sequence Motifs to Overcome Interferon-Mediated Cytotoxicity

September 6, 2017

PD-L1 is doubling down on defense. It is well-known that cancer cells often upregulate PD-L1 as a mode of defense against the immune system, however, this new research by Gato-Cañas et al. suggests that PD-L1 may also play a direct defensive role within the tumor cell by conferring resistance to IFN-mediated cytotoxicity and...

Distinct Cellular Mechanisms Underlie Anti-CTLA-4 and Anti-PD-1 Checkpoint Blockade

August 30, 2017

As the role of anti-PD-1 and anti-CTLA-4 immune checkpoint blockades (ICB) in cancer therapy continues to expand, understanding the underlying mechanisms of action becomes more imperative. Based on temporal, spatial, and cellular source differences, Wei et al. hypothesized that the anti-tumor immune responses to anti-CTLA-4 and anti-PD-1 treatment are driven by distinct mechanisms...

Constitutive IDO1 Expression in Human Tumors is Driven by Cyclooxygenase-2 and Mediates Intrinsic Immune Resistance

August 23, 2017

Cancers are the escape artists of the biological world, each with a unique act by which it eludes or overpowers the immune system of an affected organism. Some human cancers have been found to constitutively express indoleamine 2,3-dioxygenase 1 (IDO1), which rapidly catabolizes tryptophan to kynurenine, creating an immunosuppressive microenvironment that prevents T...

Multi-level Strategy for Identifying Proteasome-Catalyzed Spliced Epitopes Targeted by CD8+ T Cells during Bacterial Infection

August 16, 2017

It is well known that enzymes catalyze reactions in both directions, and so the ability of proteasomes to not only cleave larger peptides into smaller ones but also splice smaller peptides into larger ones should not be surprising; however, the biological data demonstrating this has been limited. Platteel et al. describe a multi-level...

TCR repertoire intratumor heterogeneity in localized lung adenocarcinomas: an association with predicted neoantigen heterogeneity and postsurgical recurrence

August 9, 2017

Large tumors can be difficult to address not only due to their size, but also their internal complexity and heterogeneity. Building on their previous work, in which whole exome sequencing of 2-5 spatially different regions from resected localized lung adenocarcinomas from 11 patients revealed that mutational genomic intratumor heterogeneity (ITH) was linked to...

Specificity of inhibitory KIRs enables NK cells to detect changes in an altered peptide environment

August 2, 2017

The simple hypothesis that NK cells discriminate “self” from “non-self” based on surface HLA expression understates the complexity of NK cell recognition, and now needs to be extended to include discrimination of “altered self”. As the recent study by Carrillo-Bustamante et al. suggests, changes in the peptide-ligand repertoire appear to play a role...

Landscape of Infiltrating T Cells in Liver Cancer Revealed by Single-Cell Sequencing

July 26, 2017

The more data you collect, the more details, and hopefully insights, you’ll uncover; that’s why Zheng et al. performed single-cell RNA sequencing and T cell receptor (TCR) profiling on over 5,000 individual T cells isolated from the tumors, adjacent normal tissue, and peripheral blood of six patients with hepatocellular carcinoma (HCC). From the...

Personalized Neoantigen Vaccines for High-risk Melanoma Patients

July 19, 2017

The ability to induce de novo, potent, and truly tumor-specific T cell responses as shown in two independent studies with different vaccine formats by Ott & Hu et al. (Ott&Hu) and Sahin et al. (Sahin) has the potential to transform cancer vaccination. T cells directed against neoantigens, which arise from non-silent somatic mutations...

Mitochondrial dysregulation and glycolytic insufficiency functionally impair CD8 T cells infiltrating human renal cell carcinoma

July 12, 2017

Despite extensive CD8+ T cell infiltration, clear cell renal cell carcinoma (ccRCC) responds only moderately to checkpoint blockade therapy, suggesting other immunosuppressive mechanisms. One mechanism by which tumors can avoid effector T cell function is by metabolically inhibiting the tumor-infiltrating lymphocytes (TIL). Siska et al. used a combination of mass and flow cytometry...

Depletion of tumor-associated macrophages with a CSF-1R kinase inhibitor enhances antitumor immunity and survival induced by DC immunotherapy

July 5, 2017

Malignant mesothelioma is a cancer characterized by a significant stromal component that is dominated by macrophages. Tumor-associated macrophages (TAMs) are supported by macrophage-colony stimulating factor (M-CSF), which not only enhances TAM survival and proliferation, but also their recruitment towards tumors and the expression of a pro-tumor phenotype. TAMs are linked to immune suppression...

A therapeutic T cell receptor mimic antibody targets tumor-associated PRAME peptide/HLA-I antigens

June 28, 2017

In a quest to find a highly specific, off-the-shelf cancer immunotherapy, Chang et al. designed and analyzed Pr20, a T cell receptor mimic (TCRm) antibody targeting HLA-A2 complexed with an epitope derived from the tumor-associated antigen PRAME, and presented proof of concept that TCRm antibodies have therapeutic potential in several human cancers. PRAME...

Role of CD28 in PD-1-mediated inhibition and the rescue of exhausted T cells during PD-1-targeted therapy

June 21, 2017

Although the PD-1-targeted therapies have provided clinical benefit in a variety cancers, the mechanism behind PD-1-mediated inhibition of T cells, and their subsequent rescue with PD-1-targeted therapy, is not well understood. In two separate studies, Kamphorst et al. and Hui et al. demonstrate that the CD28 costimulatory pathway plays a surprisingly important role...

Combined immune checkpoint blockade as a therapeutic strategy for BRCA1-mutated breast cancer

June 14, 2017

BRCA1 is a DNA repair gene that is commonly mutated in breast cancer patients and these tumors often exhibit a “triple negative” phenotype that limits the efficacy of several common therapies. Although cisplatin is somewhat effective as a chemotherapy against BRCA1-mutated breast cancer, the rates of drug resistance and relapse are still fairly...

Chromatin states define tumour-specific T cell dysfunction and reprogramming

June 7, 2017

It is well known that tumor-specific CD8+ T cells (TST) found within solid tumors are often dysfunctional and do not affect tumor progression. TST become dysfunctional early on in the tumorigenesis process and exhibit the same characteristics as tumor-reactive tumor-infiltrating lymphocytes (TILs) in late-stage human solid tumors. Philip et al. hypothesized that the...

STING activation reverses lymphoma-mediated resistance to antibody immunotherapy

May 31, 2017

In the context of immunotherapy, the pro- or anti-tumor activity of macrophages is a matter of nurture over nature. Macrophages in a healthy environment play a key role in inducing an adaptive immune response and clearing cellular debris; however, tumors create an immunosuppressive microenvironment that imprints a pro-tumor signature on macrophages, including a...

PD-1 expression by tumour-associated macrophages inhibits phagocytosis and tumour immunity

May 24, 2017

The presence of tumor-associated macrophages (TAMs) in a tumor microenvironment (TME) is usually associated with worse outcomes for patients. However, recent research and ongoing clinical trials have demonstrated that therapies blocking the interaction between SIRPα and CD47 can induce TAMs to phagocytose tumor cells, providing therapeutic benefit. Gordon et al. set out to...

In vivo imaging reveals a tumor-associated macrophage-mediated resistance pathway in anti-PD-1 therapy

May 17, 2017

In order to fully understand the mechanism of PD-1 checkpoint blockade therapy and potentially reduce the number of nonresponders, it is important to understand exactly what is happening in vivo. For that reason, Arlauckas et al. used intravital imaging to follow a fluorescently-labeled anti-PD-1 monoclonal antibody (mAb) in real time at a subcellular...

Single-cell RNA-seq reveals new types of human blood dendritic cells, monocytes, and progenitors

May 10, 2017

Dendritic cells (DCs) provide the critical nexus between antigenic assault and initiating adaptive immunity. DCs are well known for their antigen presentation capabilities, but when it comes to the classification of DC subtypes, the differences in function, morphology, and expression of a limited number of known surface markers provided useful but limited distinctions...

Biopolymers codelivering engineered T cells and STING agonists can eliminate heterogeneous tumors

May 3, 2017

If a problem is too big for one troop, it’s time to call for backup. While systemic injections of CAR T cells have been notably successful in the treatment of hematological malignancies, their success in solid tumors has been limited due to a number of factors, including identifying suitable targets, inefficient trafficking of...

In situ programming of leukaemia-specific T cells using synthetic DNA nanocarriers

April 26, 2017

In a new approach to CAR T cell engineering, Smith et al. skip the petri dish and head straight to the mouse. Using a stable, easy-to-manufacture nanoparticle gene delivery system, circulating T cells can be quickly programmed in vivo with CD19-targeted CARs. The nanoparticles were designed to contain two co-encapsulated DNA plasmids, one...

Landscape of Immunogenic tumor antigens in successful immunotherapy of virally induced epithelial cancer

April 19, 2017

Any good scientist knows that correlation does not necessarily equal causation. So, when two patients experienced complete remission of HPV-associated cervical cancer following adoptive therapy with tumor-infiltrating lymphocytes (TILs) that were selected for HPV reactivity, Stevanović et al. dug deeper to challenge the notion that a T cell response against the viral antigens...

Antigen presentation profiling reveals recognition of lymphoma immunoglobulin neoantigens

March 29, 2017

In an effort to discover new therapeutically useful neoantigen targets, Khodadoust et al. used new tools and found evidence for an “old” idea. In this study, the team took an integrated genomic and proteomic approach to mantle cell lymphoma from 17 untreated patients to explore the peptides presented by MHC class I and...

Targeting a CAR to the TRAC locus with CRISPR/Cas9 enhances tumour rejection

March 1, 2017

When it comes to controlling CARs it’s best to keep both hands on the wheel. In an effort to increase control in CAR T cell engineering, Eyquem et al. have utilized the CRISPR/Cas9 method to deliberately place a CD19-specific CAR coding sequence at the TRAC locus. The goal of this genetic modification was...

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