Weekly Digests

2019

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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, both...

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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