Weekly Digests

2019

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Combination ICB is greater than the sum of its parts

November 13, 2019

Anti-PD-1 and anti-CTLA-4 work through distinct mechanisms, and evidence from preclinical and early clinical trials has shown that these two checkpoint blockade therapies can be even more powerful when used in combination. To determine exactly how this combination works, Wei et al. set out to uncover whether the effects of combining anti-CTLA-4 and...

A little help from CD4+ T cells enables immunotherapy success

November 6, 2019

Aiming to understand the requirements for successful immunotherapy outcome, Alspach et al. explored the role of CD4+ T cells in antitumor response and found that expression of MHC-II neoantigens in the tumor, activation of CD4+ T cells, and CD4+ T cell help for CD8+ T cell priming and maturation were critical for response...

Make the most of what you’ve got: Vδ1+ γδ T cells

October 30, 2019

In order to effectively utilize immunotherapy against solid tumors, it is important to understand the underlying immune landscape of both tumors and the healthy tissues they grow in. To expand the understanding of the immune landscape in breast cancer, Wu and Kyle-Cezar et al. analyzed healthy and malignant breast samples from prophylactic and...

Antibodies come after TNFR2 to eradicate tumors

October 23, 2019

Searching for new cancer immunotherapies that are effective and well tolerated, Tam, Fulton, and Sampson et al. explored targeting tumor necrosis factor receptor 2 (TNFR2), which is mostly expressed on immune cells, including Tregs and activated T cells. In a paper recently published in Science Translational Medicine, the researchers generated and characterized anti-murine...

Effector or Exhausted: TCF-1 Seals T cell Fate

October 16, 2019

CD8+ T cell exhaustion plays a major role in chronic immune responses to both infection and cancer and is a major target of immunotherapy. To understand how and when exhaustion programs are initiated, Chen and Ji et al. analyzed gene expression data and transcription factor activity to define a binary fate decision early...

Anti-CTLA-4 relies on RIG-I for tumor control

October 9, 2019

Aiming to improve the consistency of response to checkpoint inhibitors, Heidegger and Wintges et al. explored how the signaling of RIG-I – a cytosolic sensor that detects double-stranded RNA during bacterial or viral infection – contributes to IFN-I production within the tumor microenvironment, and how it affects the antitumor immunity mediated by immune...

CICON19 - 5th CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference

October 2, 2019

Last week, the ACIR team attended the Fifth CRI-CIMT-EATI-AACR International Cancer Immunotherapy conference in Paris, France. This week’s extensive special feature covers select talks from the conference, which are organized by the topics below. Targeting the PD-1 axis Vaccination approachesCARs targeting solid tumors or the tumor stromaTumor and the microenvironmentMicrobiota-immune interactionsBiology of innate...

M2 to M1; macrophage reprogramming can be done!

September 25, 2019

An immunosuppressive tumor microenvironment is one of the biggest hurdles to successful immunotherapy. In many tumors, the presence of M2-polarized macrophages is to blame for immunosuppression. For Zhang et al., the possibility of reprogramming macrophages from the pro-tumor M2 phenotype to a pro-inflammatory M1 phenotype without inducing systemic inflammation was the goal in...

The CAT’s meow: low-affinity CD19 CAR T cells show strong response with low toxicity in pediatric patients with ALL

September 18, 2019

Aiming to determine how the affinity of a CAR for its target impacts efficacy and toxicity associated with CAR T cell treatment, Ghorashian et al. developed a low-affinity single-chain variable fragment (scFv) targeting CD19, compared it directly to the high-affinity scFv in a currently approved CAR product in vitro and in mice, and...

Silencing TAP makes the tumor a little louder

September 11, 2019

Tumors with high neoantigen burdens tend to respond well to immunotherapy, but patients whose tumors express few or no neoantigens may not derive the same benefits. Enhancing the immunogenicity of tumors in a way that is clinically relevant and broadly translatable could be a way to enhance immunotherapy response rates. Building on previous...

Not redundant after all: improved T cell responses with dual PD-1 axis blockade in pancreatic cancer

September 4, 2019

Aiming to elucidate the role that neoantigens play in the response of pancreatic ductal adenocarcinoma (PDA) to immunotherapy, particularly in a subset of patients with PDA that is infiltrated by T cells, Burrack et al. developed a new mouse model expressing a neoantigen to study the fate of tumor-specific CD8+ T cells during...

Targeting CD30 helps dual-specificity CAR T cells improve themselves

August 21, 2019

In the hunt to expand the arsenal of checkpoint regulators, Hombach et al. investigated the possibility of targeting the CD30-CD30L axis. CD30 and/or CD30L can be expressed on a number of immune cells (T cells, B cells, and some APCs), and prior evidence has suggested that it may play a role in limiting...

The interferon seesaw between tumor cells and immune cells determines response to immune checkpoint blockade

August 14, 2019

Interferon is full of paradoxes. Some patients have cancers with a mutated IFN pathway, but still respond to immune checkpoint blockade (ICB). Other patients have high serum levels of IFNγ, but their cancer progresses with ICB treatment. IFNγ can boost immune function, but also promotes T cell exhaustion via upregulation of PD-L1. In...

The timing of priming and PD-1 blockade

August 7, 2019

Checkpoint blockade of the PD-1 axis (PD-1 or PD-L1) can be effective in inducing antitumor immunity, although many patients still relapse or fail to derive clinical benefit at all. Combinations of anti-PD-1 treatment with vaccines against tumor-associated antigens or with other immunomodulatory agents are actively being explored, and optimal timing and sequencing have...

CAR T cells get a boost inside lymph nodes

July 31, 2019

With the goal of improving the efficacy of CAR T cells in solid tumors and enhancing their functional persistence in all types of malignancies, Ma et al. developed a strategy to target CAR-detectable ligands to the lymph nodes in order to expand CAR T cells in the native lymph node environment. The results...

Reduce, Reuse, Recycle to improve anti-CTLA-4 therapy

July 24, 2019

Targeting the checkpoint molecule CTLA-4 using antibodies has been relatively successful as a cancer immunotherapy, however, clinical benefits often come with severe and sometimes dose-limiting immune-related adverse events (irAEs). In a paper recently published in Cell Research, Zhang, Du, and Liu et al. investigated why different CTLA-4 targeting antibodies induce different degrees of...

Cancer escapes before you know it’s there

July 17, 2019

With the goal of detecting and treating cancer as early as possible, Mascaux and Angelova et al. analyzed biopsies of premalignant and malignant lesions from patients who ultimately developed lung squamous cell carcinoma (SCC), and found that immune activation and subsequently immune escape occur in the pre-invasive stages of carcinogenesis. The results were...

Activation and exhaustion in adaptive NK cells

July 10, 2019

It is well known that chronic stimulation of the TCR on T cells leads to activation and exhaustion, but the effect of chronic stimulation on NK cells is not as well understood. To investigate this, Merino et al. induced chronic stimulation in CD3-CD56dimCD57+NKG2C+ NK cells, deemed “adaptive” NK cells, which have a genetic...

TOX is so exhausting!

July 3, 2019

In this special feature, we summarize five recently published papers that explore the role of the transcription factor TOX in exhausted CD8+ T cells, which are common in cancer and chronic infections, and are the major target of checkpoint blockade. Although the research groups utilized different models (acute infection, chronic infection, tumors) and...

4-1BB agonism that only works on site

June 26, 2019

4-1BB plays an important role in the costimulation of T cells and is an attractive target for immunotherapy, however, clinical targeting of 4-1BB using agonistic antibodies has been plagued by either low potency or off-target liver toxicity due to Fcγ receptor (FcγR)-mediated cross-linking. To overcome these challenges and induce tumor-localized T cell costimulation...

Tumor infiltration is governed by CCL5 and CXCL9

June 19, 2019

Patients whose tumors are strongly infiltrated by immune cells tend to have a better prognosis and better responses to immunotherapy, but the mechanisms that underlie immune infiltration are not clearly defined. To better understand the infiltration of T cells into tumors, Dangaj et al. investigated the roles of chemokines in the tumor microenvironment...

Tregs eat costimulatory ligands to prevent T cell activation

June 12, 2019

It is well-known that Tregs suppress T cell responses to self-peptides via the CTLA-4 pathway in order to maintain normal immune homeostasis, but the details of this mechanism have not been fully elucidated. In vitro studies have shown that Tregs suppress the CD28-dependent activation of naive T cells by limiting their access to...

Multispecific antibodies set the rules of engagement for NK cell-mediated tumor control

June 5, 2019

Many bispecific T-cell engager antibodies have been developed and tested in recent years, but challenges with off-target toxicities and lack of efficacy against solid tumors remain. Instead of targeting T cells for antitumor immunity, Gauthier et al. designed and developed trifunctional NK-cell engagers (NKCEs) with the goal of reducing off-target cytotoxicity and enabling...

Turning Tregs From Enemies to Allies

May 29, 2019

T regulatory cells (Tregs) are known for their ability to suppress effector T cell functions in the tumor microenvironment. In an effort to better understand and possibly disrupt Treg-mediated immunosuppression, Di Pilato and Kim et al. investigated the CARMA1-BCL10-MALT1 (CBM) signalosome complex within Tregs. Interestingly, disruption of the CBM complex in all or...

Why does PD-1 blockade need CXCR3 signaling? It’s not what you think

May 22, 2019

Motivated to extend the benefit of PD-1 blockade to more patients, Chow et al. explored the role that chemokines play in resistance to anti-PD-1 and found that the chemokine receptor CXCR3 and its ligand CXCL9 were crucial for the response to anti-PD-1 therapy in mouse tumor models. The results were recently published in...

CTLA-4 and PD-1 set the limits on T cell differentiation

May 15, 2019

Positive and negative costimulatory molecules on T cells are known to play a role in T cell activation, however, whether they play a role in T cell differentiation (along with TCR signal strength and cytokine signaling) is not as well defined. Following observations that genetic loss or blockade of CTLA-4 can affect CD4+...

Targeting tumor collagen hits the immunotherapeutic sweet spot

May 8, 2019

While immune checkpoint inhibitors and cytokine treatments have demonstrated efficacy against several types of cancer, they frequently cause severe side effects due to excessive and widespread off-tumor activation of the immune system. In a paper recently published in Science Translational Medicine, Ishihara and Ishihara et al. aimed to decrease off-tumor toxicities by taking...

Too much of a good thing: why KIT inhibitors stop working

May 1, 2019

Constitutive signaling from a single mutation in the KIT proto-oncogene can be sufficient to drive the formation of a gastrointestinal stromal tumor (GIST). These tumors constitutively express immunosuppressive IDO, which dampens dendritic cell-primed effector CD8+ T cell responses. Previous studies have suggested that using imatinib, a small molecule Kit inhibitor that dampens IDO...

The priming power of cDC2s

April 24, 2019

While researchers often focus on CD8+ T cells in antitumor immunity, many studies have shown critical roles for CD4+ T cell responses as well. In order to better understand the context in which antitumor CD4+ T cell responses are initiated, Binnewies and Mujal et al. examined a variety of cell types and factors...

Potassium determines the fate of T cells

April 17, 2019

In a paper recently published in and featured on the cover of Science, Vodnala and Eil et al. investigated why some patients have dysfunctional tumor-infiltrating lymphocytes (TILs), while others have T cells that behave like stem cells in their capacity to self-renew, proliferate, and destroy large tumors. They found that this difference is...

AACR Annual Meeting 2019

April 10, 2019

Last week, the ACIR team attended the AACR Annual Meeting 2019 in Atlanta, Georgia. This week’s extensive special feature covers select talks from the conference. We have organized the content by topics below. T cells in Immune surveillance, Exhaustion, and TherapiesEmerging Immunotherapy ApproachesTME and Tumor EscapeClinical Trials T cells in Immune surveillance, Exhaustion...

Targeting macrophages and neutrophils enhances response to chemotherapy

April 3, 2019

Previous research has shown that the immune system contributes to chemotherapy response; therefore, immunosuppressive mechanisms can be hypothesized to limit the cytotoxic effect. In a study recently published in Nature Cell Biology, Salvagno et al. demonstrated that targeting immunosuppressive macrophages and neutrophils enhances the efficacy of platinum-based chemotherapy in a mouse breast cancer...

An “IF/THEN” CAR T cell that targets only the tumor

March 27, 2019

CD19-targeted CAR T cells can be incredibly effective against B cell malignancies, however, they do not discriminate between malignant and healthy cells. In the case of lineage-restricted CD19, the killing of on-target, off-tumor cells is not a major problem because patients can survive without B cells. A major challenge in treating solid tumor...

Siglec-15 suppresses T cell antitumor response

March 20, 2019

To improve the response rate to cancer immunotherapies, Wang and Sun et al. sought to identify factors beyond the PD-1 axis and other known checkpoint inhibitors that may affect T cell function. Utilizing a high-throughput screening approach as well as in vitro and in vivo studies, the researchers identified Siglec-15 as a suppressor...

NR4A transcription factors control T cell dysfunction programs

March 13, 2019

T cell dysfunction – in the form of exhaustion, anergy, or tolerance – is known to limit the effector functions of T cells, but the molecular mechanisms that induce dysfunctional programs are not fully understood. Two recent studies, published back-to-back in Nature, investigated the mechanisms underlying T cell dysfunction, and through different strategies...

TAMs may be friends, not foes, in early-stage tumor T cell response

March 6, 2019

Knowing that immunotherapy that works in mice often fails in patients with solid tumors, and that mouse models mostly utilize tumor cell lines from advanced tumors, Singhal et al. decided to bypass murine studies entirely and instead analyzed the functions of macrophages and monocytes and their interactions with tumor-specific T cells within early-stage...

Boosting immunity with the microbiome

February 27, 2019

In recent years, the microbiome has gained increased attention for its effects on the immune system, and it is well known to influence the CD4+ T cell compartment; however, little is known of its effect on CD8+ T cells. In a study recently published in Nature, Tanoue and Morita et al. show that...

Found: tumor-reactive regulatory T cells

February 20, 2019

Elevated levels of CD4+ regulatory T cells (Tregs) are often found in human tumors and are associated with poor prognosis. However, the antigen specificity of intratumoral Tregs is not well understood. In a paper recently published in Science Immunology, Ahmadzadeh et al. analyzed the relationships of TCR sequences between intratumoral FOXP3+ Tregs, circulating...

Tcf1+ progenitor-like T cell subsets sustain antitumor responses

February 13, 2019

Two articles, recently published back to back in Cell, identify important roles for T cells expressing Tcf1 (encoded by Tcf7), a transcription factor known to play roles in maintaining a relatively undifferentiated T cell state, promoting self-renewal and T cell memory. Kurtulus and Madi et al., working primarily with the MC38-OVA colon carcinoma...

Koch Institute Immune Engineering Symposium 2019

February 6, 2019

Last week, the ACIR team attended the Koch Institute Immune Engineering Symposium in Cambridge, Massachusetts. This week’s extensive special feature covers select talks from the conference. Robert Schreiber opened the symposium by examining the role of MHC II and CD4+ T cells in tumor control, particularly with the backdrop that many tumors do...

Dysfunction: what’s in a name?

January 30, 2019

To gain insight into the mechanisms underlying response and resistance to immunotherapy, Li, van der Leun, Yofe, and Lubling et al. set out to molecularly characterize the expressed gene sets of tumor-infiltrating immune cells in order to quantitatively and qualitatively analyze the heterogeneity within and between cancer patients. The results were recently published...

Communication is key in PD-1 blockade

January 23, 2019

The efficacy of immunotherapy is dependent on a variety of factors and cells in the tumor microenvironment, and understanding these complex interactions is critical to understanding and improving the efficacy of treatment. To study some of these interactions, Garris and Arlauckas et al. used real-time intravital imaging, RNA sequencing, and a series of...

NKG2A blockade releases the brakes on CD8+ T cells and NK cells

January 16, 2019

With the success of immune checkpoint blockade in some cancer patients, but failure in many others, scientists are always on the lookout for new checkpoints to target. The inhibitory receptor NKG2A is found on many NK cells and few CD8+ T cells in peripheral blood. It heterodimerizes with CD94 and, upon binding its...

The shape of intratumor heterogeneity

January 9, 2019

Most tumors exhibit a high degree of genetic and functional heterogeneity, but how that heterogeneity is established and evolves in situ under immune pressure has been difficult to study. To tackle this obstacle, Milo et al. established a mouse model of MYC-driven B cell lymphoma with a large degree of genetic diversity, both...

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