Weekly Digests

2020

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Delivery routes for better T cell outcomes

November 18, 2020

Personalized cancer vaccines have demonstrated safety and potency in early clinical trials; however, the magnitudes of T cell responses have been limited, and definitive positive clinical effects have not been demonstrated. These results suggest that improving the magnitude may be beneficial, and that the quality of vaccine-responding T cells must also be considered...

Directing the dendritic cell response with ISIM

November 11, 2020

T cells get a lot of attention in cancer immunotherapy, but dendritic cells are what drive T cell responses forward. Honing in on strategies that kickstart dendritic cells to induce strong antitumor T cell responses in otherwise cold tumors, Oba and Long et al. designed a rational, multi-step combination therapy called in situ immunomodulation...

ICOSL expression crucial for DC vaccines

November 4, 2020

Even though therapeutic dendritic cell-based vaccines are immunogenic, clinical responses to these therapies are often minimal. To address this issue, Maurer et al. focused on comprehensively examining the characteristics of DCs used in such vaccines to determine whether patient-specific characteristics affect efficacy. As a DC source, the researchers turned to samples available from...

AACR Tumor Immunology and Immunotherapy 2020

October 28, 2020

Last week, the ACIR team attended the AACR Tumor Immunology and Immunotherapy conference that virtually took place in Boston, MA. This week’s extensive special feature covers select sessions from the conference. We have organized the content by topics below. Approaches to T cell priming and vaccines Regulators of tumor immunityMyeloid Compartment in the TMECAR...

Intracellular PD-L1 signaling guides the DC home

October 21, 2020

While the effect of PD-1 signaling in T cells in response to binding with PD-L1 has been reasonably well established, PD-L1 signaling via its cytoplasmic domain, so-called PD-L1 reverse signaling, has not been broadly studied. In tumor cells, PD-L1 reverse signaling protects the cells from IFN-induced cell death, but its effects on antigen-presenting...

A new internal T cell checkpoint: CISH

October 14, 2020

PD-1 and other known markers of activation and exhaustion have helped researchers to understand T cell biology and develop numerous immunotherapies. While many of these markers are well known and well studied, there are likely more that have yet to be investigated. Looking into the relationship between PD-1 and other markers of activation...

PD-L1 and PD-1 mediate T cell suppression, but not where you think

October 7, 2020

Targeting the PD-1/PD-L1 axis is a common immunotherapeutic strategy that works well in some, but not all patients with cancer. Typically, researchers have looked at interactions between PD-1 and PD-L1 within tumors to explain the mechanism behind this treatment; however, this has never fully explained the efficacy, or lack thereof, of PD-1/PD-L1 blockade...

An unconventional cDC outcome of IL-2 immunotherapy

September 30, 2020

Interleukin-2 (IL-2) treatment was the first FDA-approved cancer immunotherapy, achieving robust and curative responses in metastatic melanoma and renal cell cancer in the 1980s-90s and paving the way for advances in the decades since [1]. Mechanistically, IL-2 has been understood to primarily influence T cell expansion and activation. However, the role of IL-...

Local glucocorticoid production results in dysfunctional T cells in the tumor

September 23, 2020

One of the ways the tumor microenvironment (TME) shapes the antitumor immune response is through triggering the presence of exhausted, dysfunctional CD8+ tumor-infiltrating lymphocytes (TILs). Many of the factors contributing to the induction of dysfunctional cells remain largely unknown, but could serve as novel immunotherapy targets. Acharya and Madi et al. recently described...

IFNγ signaling paves the way for effective checkpoint blockade

September 16, 2020

In recent years, researchers have made much progress in understanding the therapeutic response to checkpoint blockade strategies, but to further improve the success rate, clues might be found in a deeper investigation of the mechanisms behind the response. In a recent publication in Cancer Cell, Grasso et al. describe their analysis of a...

Early antigen exposure sets a predetermined path towards T cell exhaustion

September 9, 2020

In past studies, researchers have identified a subset of T cells that serve as precursors to exhausted T cells. While these cells show some features of exhaustion, they maintain high proliferative potential and are able to both self-renew and replenish populations of exhausted effector T cells that mediate control in chronic viral infections...

Stromal cells affect immune infiltrate in triple-negative breast cancer

September 2, 2020

As one of the the main components of tumor stroma, cancer-associated fibroblasts (CAFs) play essential roles in the tumor microenvironment (TME), including in remodeling of the extracellular matrix, metastasis, and inflammation, making them interesting therapeutic targets. However, much remains unknown about their phenotypes, functions, and relationships with the immune infiltrate. In work recently...

cDC1s take on double duty, priming both CD8+ and CD4+ T cells

August 26, 2020

In the currently understood paradigm of T cell priming, it has generally been assumed that cDC1s cross-present peptides on MHC-I to prime CD8+ T cells, while cDC2s, which express high levels of MHC-II,  present antigens on MHC-II to prime CD4+ T cells. CD4+ T cells are then thought to license cDC1s, supporting CD8+...

Remodeling tumor macrophages for effective checkpoint blockade therapy

August 19, 2020

While immune checkpoint therapy (ICT) has successfully treated a wide array of cancers, the majority of patients do not benefit. This may, in part, be due to immune suppression within the tumor microenvironment (TME), relying on certain myeloid cell populations that can dampen T cell immunity and aid tumor progression. In work recently...

RNA vaccine for melanoma shows promise in early clinical trial

August 12, 2020

In the world of cancer vaccines, targeting tumor-associated antigens (TAAs) has historically yielded only weak immune responses. In an effort to improve vaccine targeting of TAAs, researchers developed a nanoparticulate liposomal RNA (RNA-LPX) that targeted dendritic cells in vivo and induced antigen presentation on HLA-I and HLA-II molecules in lymphoid compartments in mice...

Off-the-shelf allogeneic CAR-T cells one step closer to becoming a reality

July 29, 2020

With many CAR T cell strategies in development and successful trials piling efficacy data, the need arises to make these strategies more widely available. Cell manufacturing is costly and demands highly skilled personnel. Methods allowing a less personalized, but rather “off-the-shelf” approach in which CAR-T manufactured from healthy donor T cells can be...

PRMT5 inhibition warms up cold tumors and leads to PD-1 blockade response

July 22, 2020

Aiming to more fully understand the mechanisms underlying the resistance of tumors to immune checkpoint blockade, Kim et al. explored the role that the epigenetic modifier PRMT5 (protein arginine methyltransferase 5), which regulates processes related to oncogenesis, may play in enabling immunosuppression in melanoma. The results, recently published in Science Translational Medicine, demonstrate...

PD-1 signaling aids in memory T cell formation

July 15, 2020

The PD-1 axis plays an important role in regulating the activation of T cells, and blockade of the PD-1 axis has had profound clinical significance over the past decade. Although multiple studies have investigated the impact of PD-1 signaling during the early stages of an immune response and on the rescue of “exhausted”...

PD-L1 on dendritic cells controls the antitumor response

July 8, 2020

PD-1 axis blockade has been proven time and again to be a successful immunotherapy for a wide variety of cancer types, and it is assumed to work by reversing or preventing T cell exhaustion. However, the exact way by which this cancer immunotherapy works has not been fully elucidated, and recent studies have...

MAIT cells: linking the gut microbiome to antitumor immunity?

July 1, 2020

In patients with colon adenocarcinoma, high infiltration by mucosa-associated invariant T (MAIT) cells – which can be activated by a wide variety of bacteria and recognize epitopes presented by the MHC-like molecule using a limited set of invariant/preferential TCRs – have recently been associated with poor clinical outcomes. In a study recently published...

Messenger for DCs: vesicles spread tumor antigens across dendritic cell subsets

June 17, 2020

It is well known that the initiation of an antitumor T cell response begins with priming by dendritic cells (DCs) inside the tumor-draining lymph node (TDLN). But how do migratory DCs, which pick up antigens at the tumor site, transfer the tumor antigens to LN-resident DCs and enable T cell priming? To answer...

CD4+ T cells take center stage in bladder cancer

June 11, 2020

Bladder cancer is often resistant to anti-PD-1 immunotherapy, however, responses do occur in a small fraction of patients. In order to better understand the specific T cells that mediate tumor rejection in those infrequent cases, Oh and Kwek et al. used single-cell RNAseq and TCRseq to profile T cells from muscle-invasive bladder tumors...

Flt3L-armored T cells engage the immune system to fight solid cancers

June 3, 2020

As tumor antigen heterogeneity limits the efficacy of engineered TCR and CAR T cells against solid tumors, Lai and Mardiana et al. engineered T cells that express and secrete the dendritic cell (DC) growth factor Flt3L in order to more fully engage the endogenous immune system in the fight against the cancer. The...

High IL-8 correlates with reduced response to PD-1/PD-L1 checkpoint blockade

May 27, 2020

When it comes to improving cancer immunotherapy, finding strong biomarkers and finding novel targets are both key goals. In two papers recently published back-to-back in Nature Medicine, Yuen and Liu et al. and Schalper and Carleton et al. identify IL-8 (also known as CXCL8) both as a predictive biomarker of reduced clinical benefit...

Exhausted T cells come in many flavors

May 20, 2020

Aiming to improve clinical response to immunotherapy by better understanding the mechanisms behind the development of the heterogeneous population of exhausted CD8+ T cells (Tex), Beltra et al. extensively analyzed Tex cells in a chronic infection setting. The researchers identified four subsets with distinct transcriptional, epigenetic, and phenotypic features, as well as elucidated...

MDSCs play metabolic freeze tag with T cells

May 13, 2020

Suppressive myeloid cells, namely myeloid-derived suppressor cells (MDSCs), are known to appear in situations of chronic inflammation and cancer, where they suppress cytotoxic T cell responses. However, without an existing definitive marker for this immune subset, MDSCs can be difficult to study and target. In research recently published in Nature Immunology, Baumann et...

Engineering a safer, more potent IL-2

May 6, 2020

Recombinant human interleukin-2 (rhIL-2, aldesleukin) was approved decades ago for the treatment of cancer, and it induces long-lasting, sometimes complete responses in a subset of patients with metastatic melanoma or metastatic renal cell carcinoma. However, due to the risk of capillary leak syndrome and associated toxicities, the use of rhIL-2 treatment has been...

Interferon-III interferes with breast cancer

April 29, 2020

Dendritic cells play a critical role in kickstarting immune responses, and cDC1s, which cross-present antigens and activate CD8+ T cells, are of particular interest for inducing responses to immunotherapy. Previous research has shown tumor infiltration by cDC1s to be associated with favorable patient prognoses and improved clinical responses to anti-PD-1. In a paper...

Just a few neoantigens may be enough for T cells to control prostate cancer

April 22, 2020

Can checkpoint blockade benefit patients whose cancers have low tumor mutational burden? To address this question, Subudhi et al. conducted a phase II clinical trial of patients with advanced prostate cancer – a cancer known to have a relatively low mutational load – who were treated with ipilimumab, and evaluated their treatment-induced immune...

It’s best to be selective – targeting TGFβ1

April 15, 2020

TGFβ is known to play a role in immunosuppression and resistance to immune checkpoint blockade, however, efforts to block TGFβ to enhance immunotherapy have been limited by cardiotoxicity. TGFβ exists in three isoforms – TGFβ1, TGFβ2, and TGFβ3 – and while TGFβ2 and TGFβ3 have been linked to cardiac function, TGFβ1 has not...

Vaccine + chemo activate immune response against cervical cancer

April 8, 2020

While a therapeutic human papilloma virus type 16 (HPV16) vaccine can effectively promote an immune response and subsequent durable regressions of HPV16-induced premalignant lesions, it has shown no clinical benefit in patients with late-stage HPV16-induced cervical cancer. To address the immunosuppressive environment that prevents the vaccine from inducing a strong immune response in...

Release the B7.1! Anti-PD-L1 breaks PD-L1’s grip

April 1, 2020

Blocking the PD-1/PD-L1 axis using anti-PD-L1 antibodies is a commonly employed immunotherapeutic strategy to prevent PD-1-mediated inhibition of T cells by tumor cells. Suspecting that the mechanism of action of PD-L1 blockade might be more complex, however, Mayoux et al. investigated the role of PD-L1-expressing dendritic cells (DCs) in PD-L1 blockade. The results...

Special announcement

March 25, 2020

To All Our Readers, The COVID-19 crisis has dominated the world's attention and caused major changes in all our lives. To give our team members the chance to adjust to this ever-intensifying landscape we decided to take a brief 2 week pause in publishing our newsletter. Despite this pause, our staff and our volunteers...

Bee venom throws a one-two punch to kill the tumor

March 18, 2020

Targeting the tumor where it lives and turning the tumor against itself was what Yu and Dai et al. had in mind when they developed a one-two punch nanovaccine comprising a lipid nanoparticle (NP) loaded with melittin (a peptide found in European bee venom), called α-melittin-NP. The vaccine, which contained no tumor antigens...

Put me in, coach! Peripheral T cells are ready to play

March 11, 2020

In an effort to investigate the origin, behavior, and fate of T cells in patients with cancer, Wu et al. sequenced 330 million mRNA transcripts from 141,623 T cells, which had been isolated from the tumors and normal adjacent tissue (NAT) of 14 treatment-naive patients with 4 different types of cancer; peripheral blood...

Zeroing in on intratumoral Tregs via CD36

March 4, 2020

With the goal of selectively disrupting intratumoral Tregs without inducing systemic autoimmunity, Wang et al. hypothesized that intratumoral Tregs must metabolically adapt to the harsh conditions of the tumor microenvironment (TME), and therefore explored metabolic pathways that could potentially target Tregs exclusively within the TME to find actionable targets. The results, recently published...

T cells CRISPRed to perfection for attack on refractory cancer

February 26, 2020

Aiming to improve the safety and efficacy of engineered T cells for the treatment of human cancers, Stadtmauer and Fraietta et al. utilized CRISPR-Cas9 genome editing to knock out PD-1 (PDCD1) and the endogenous TCR α and β chains (TRAC and TRBC) in autologous T cells that also expressed an exogenous TCR targeting...

CAR NK cells – the newest drivers on the road

February 19, 2020

The powerful effects of CD19-targeting CAR T cells against blood cancers have been well documented in a high portion of treated patients. However, CAR T cells can induce significant toxicities, and the fact that this treatment must be personalized makes the manufacturing process slow, challenging, and expensive. In early results from a phase...

Bispecific antibody 7370: will AML meet its match?

February 12, 2020

In an effort to address the significant unmet clinical needs in the treatment of acute myeloid leukemia (AML), Yeung and Krishnamoorthy et al. developed a novel bispecific antibody that targets both CD3 on T cells and FLT3 on AML cells. FLT3 was selected as a strong potential target antigen, given its upregulated expression...

The holy grail: pan-cancer-targeting T cells

February 5, 2020

The holy grail of cancer research is finding one treatment that kills all types of cancer in every affected individual. With this lofty goal in mind, Crowther and Dolton et al. explored unconventional T cells and identified a T cell clone capable of killing many different types of cancer in an HLA-independent fashion...

Special delivery! An oncolytic virus encoding IL-7 and IL-12

January 29, 2020

The immune status of the tumor microenvironment (TME) is known to be a key factor influencing the success or failure of cancer immunotherapy. In an effort to improve the immune status of the TME, Nakao et al. tested the intratumoral delivery of oncolytic viruses encoding IL-7 and IL-12, and saw encouraging local and...

PD-1 in myeloid cells prevents tumor control

January 22, 2020

Aiming to uncover the role that the expression of PD-1 in various cell types plays in antitumor immunity, Strauss et al. analyzed the effects of selective PD-1 ablation in myeloid cells and T cells, and surprisingly found that knockout of PD-1 in myeloid cells, but not in T cells, was crucial for an...

Kickstarting the cancer immunity cycle with AGI-134

January 15, 2020

The cancer immunity cycle starts and ends with cancer cell death, and inducing cancer cell death at the site of a tumor to kickstart antitumor immunity is a developing strategy in cancer immunotherapy. One approach that has been explored to induce cancer cell death in situ is the introduction of α-Gal epitopes, which...

Stem-like CD8+ T cells cozy up within tumors before launching an attack

January 8, 2020

Since the infiltration of CD8+ T cells into tumors predicts survival and response to immunotherapy in many patients, Jansen et al. examined the CD8+ T cell response against human cancer in order to understand why some tumors have high CD8+ T cell infiltration while others do not, and to uncover the mechanisms behind...

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