Weekly Digests

2024

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Timing is everything when combining radiation and immunotherapy

July 17, 2024

Even though the combination of radiotherapy and immune checkpoint blockade (ICB) has great potential to work synergistically, clinical efficacy has been limited. Irradiation of the draining lymph nodes (dLNs) to target metastases might be to blame for this, as these are essential places for antigen presentation and priming of T cells, needed for...

A closer look at inflammation suggests new treatment approach for PDAC

July 10, 2024

Pancreatic ductal adenocarcinoma (PDAC) remains refractory to immunotherapy due to a compromised tumor immune microenvironment (TIME) with dysfunctional T cells, suppressive myeloid and regulatory T cells (Tregs), and a sparsity of neoantigens and antigen-presenting cells. Patients with a history of chronic pancreatitis have an increased risk of developing PDAC, and progression of pancreatic...

JAK-ing up ICB responses with JAK inhibitors

July 3, 2024

One of the main outstanding issues for cancer immunotherapy is how to improve the efficacy of immune checkpoint blockade (ICB) in subsets of patients who currently do not benefit. Two recent back-to-back publications in Science tackled this issue by combining ICB with JAK inhibition. Zak, Pratumchai, Marro, et al. performed preclinical and clinical...

Three’s company: immune triads license CD8+ T cell-mediated antitumor immunity

June 26, 2024

CD4+ T cells are known to “help” CD8+ T cells by licensing their cytotoxic functions in tumors, but exactly how this help is given is not entirely understood. To better understand how CD4+ T cells contribute to CD8+ T cell responses, Espinosa-Carrasco et al. developed a tumor and adoptive cell therapy (ACT) model...

Shaping immunity: how tissue confinement impacts DC function

June 19, 2024

Immune cells shift shapes as they travel through the body’s tissues. Shape-sensing pathways play a role in adapting to these deformations, but it remains unknown how shape sensing affects immune function. Alraies et al. recently published data in Nature Immunology on changes to the immune function of dendritic cells (DCs) while undergoing cell...

Strong and steady: robust TCR stimulation supports Tpex cell formation and maintenance

June 12, 2024

Progenitor exhausted T cells (Tpex), marked by high expression of Tcf1, Tox, and Ly108, help to replenish and maintain effector T cells in tumors, allowing for strong and sustained antitumor functions, including in the context of immunotherapy responses. However, exactly how these cells acquire and maintain this functional phenotype, and whether TCR engagement...

Age is not just a number: age-related dysfunctional T cell subset restricts antitumor responses

June 5, 2024

Aging is known to induce immune dysfunction in cancer, but the mechanisms behind it remain poorly understood. In a recent Nature Immunology publication, Chen et al. assessed tumor-infiltrating T cells and the tumor microenvironment (TME) of young and aged mice to determine how age-related dysfunction relates to chronic stimulation-induced T cell exhaustion. To...

RIGging the game: LRIG1 induces CD8+ T cell quiescence by engaging VISTA

May 29, 2024

Immune checkpoint inhibitors have revolutionized the cancer immunotherapy field, and V domain immunoglobulin suppressor of T cell activation (VISTA) has garnered attention as a potentially relevant immune regulatory molecule. In preclinical models, VISTA blockade has promoted CD8+ T cell infiltration and inflammatory cytokine secretion in tumors, leading to antitumor efficacy. VISTA appears to...

A glucocorticoid game changer for B cell cancers

May 22, 2024

Glucocorticoids are used in combination with chemotherapy and rituximab for the treatment of B cell malignancies, such as diffuse large B-cell lymphoma (DLBCL), chronic lymphocytic leukemia (CLL), follicular lymphoma (FL), and acute lymphoblastic leukemia (ALL). They function as glucocorticoid receptor (GR) agonists to act on downstream signaling related to cell cycle progression and...

TMEs show night and day differences in accordance with circadian rhythms

May 15, 2024

Circadian rhythms allow organisms to operate on 24-hour cycles and coordinate periods of activity and rest in response to light and dark. These oscillations, controlled by both internal and external “clocks”, have also been shown to impact various aspects of the immune system, including responses to vaccines and tumor immune infiltration. To extend...

PGE(2) sabotages TIL expansion and effector differentiation

May 8, 2024

The bioactive lipid prostaglandin E2 (PGE2) is often detected in the tumor microenvironment (TME), and has been shown to play a role in immune escape and cancer progression. Two recent studies published in Nature assessed the effects of PGE2 on tumor-infiltrating lymphocytes (TIL). Lacher, Dörr, et al. investigated its impact on TCF1+CD8+ T...

Targeting IL-2 to CD8+ T cells enhances its benefits while reducing its risks

May 1, 2024

IL-2 is one of the earliest immunotherapeutic agents to induce complete responses in patients with cancer, but its use has been limited by its toxicity and the need for frequent administration. In order to capitalize on the desirable effects of IL-2 while limiting its risks, Moynihan et al. set out to investigate ways...

Personalized neoantigen vaccine improves anti-PD-1 in advanced hepatocellular carcinoma in early clinical trial

April 24, 2024

Advanced hepatocellular carcinoma (HCC) is a tumor type with a modest tumor mutation burden (TMB), low T cell infiltration, limited responses to checkpoint inhibitors, and a low patient survival rate. To overcome these hurdles, Yarchoan et al. conducted a single-arm, open-label, phase 1/2 study, in which 36 patients with advanced HCC who had...

AACR Annual Meeting 2024

April 17, 2024

Last week, the ACIR team attended the AACR Annual Meeting 2024 in San Diego, California. This week’s extensive special feature covers select talks from the conference. We have organized the content by topics below. AACR-Cancer Research Institute Lloyd J. Old AwardGordon J. Freeman Regulation of anti-tumor immunitySébastien TalbotStefani SprangerDmitry I. GabrilovichJustin Micah BalkoSjoerd...

KEYSTONE SYMPOSIA: Beyond Immune Checkpoint Blockade and Overcoming Resistance

April 10, 2024

The ACIR team attended the Keystone Symposia on Cancer Immunotherapy: Beyond Immune Checkpoint Blockade and Overcoming Resistance held on March 17-20, 2024 in Whistler, BC, Canada. This week’s extensive special feature covers select talks from the conference. We have organized the content by topics below. (This Keystone Symposia conference is available for On...

Macrophage makeover required for effective CTLA-4 and ICOS combination therapy

April 3, 2024

Having previously shown that ICOS stimulation via an ICOSL-transduced B16F10 cellular vaccine (IVAX) works synergistically with CTLA-4 immune checkpoint blockade (ICB) in various murine tumor models, Sharma et al. set out to explore the mechanism of action of this synergy. In a recent publication in the Journal of Experimental Medicine, they described their...

Stem-immunity hubs predict response to anti-PD-1 in NSCLC

March 27, 2024

Chen, Nieman, and Spurrell et al. recently evaluated multicellular “immunity hubs” in samples of human non-small cell lung cancer (NSCLC) taken prior to treatment with anti-PD-1. Using imaging techniques and spatial transcriptomics, the researchers identified and characterized novel “stem-immunity hubs” that were strongly associated with PD-1 blockade responses and outcomes. Their results were...

T cells and macrophages collaborate to overcome MHC-I loss-induced immune deserts

March 20, 2024

Loss of MHC class I expression on tumor cells is a frequently observed immunotherapy resistance mechanism. The increased use of immune checkpoint blockade (ICB) for the treatment of solid tumors has resulted in more therapy-resistant MHC-I-deficient tumors. To better understand the mechanisms behind these effects and determine how to overcome this response, Beck...

CD4+ T cells help cDC1s provide CD8+ T cells with a license to kill

March 13, 2024

CD4+ T helper cells can stimulate CD8+ T cell responses by interacting with dendritic cells (DCs) through a process termed “DC licensing”. The conventional type 1 DC (cDC1) subset has been identified as the essential DC subtype for this process. Lei et al. investigated the mechanism of cDC1 licensing in human cells and...

ESMO Targeted Anticancer Therapies Congress 2024

March 6, 2024

The ACIR team attended the ESMO Targeted Anticancer Therapies Congress 2024 in Paris, France. This week’s extensive special feature covers select talks from the conference. We have organized the content by topics below. Keynote lecture on tumor neoantigensYardena Samuels BispecificsJuanita S. LopezShohei KoideGeorg Falck Antibody-drug conjugatesTakashi KagariGiuseppe CuriglianoBarbara PistilliToshio Shimizu Targeted interleukinsGiuseppe CuriglianoIgnacio...

MEGA news in gene editing: using new CRISPR technology for RNA knockdown

February 28, 2024

The CRISPR-Cas9 gene editing platform has revolutionized research and medicine by allowing for precise editing of DNA. However, these systems cannot be dynamically regulated and have limitations in their safety and efficacy. To overcome some of these limitations, Tieu et al. developed multiplexed effector guide arrays (MEGA) – a CRISPR-Cas13d platform that targets...

Taking tips from T cell cancers to improve T cell therapies

February 21, 2024

T cell therapies have been used to treat numerous cancers, but they are often limited by poor proliferation, limited persistence, immunosuppressive tumor environments, and exhaustion. In order to overcome some of these limitations, Garcia and Daniels et al. investigated naturally occurring mutations in T cell neoplasms (including clonal cells from autoinflammatory conditions and...

Antigen-specific T cells in blood predict anti-PD-1 responses in Merkel cell carcinoma

February 14, 2024

Tumor antigen-specific CD8+ T cells are known to be important in antitumor immunity, but identifying them in patient samples is often a challenge. In order to study tumor antigen-specific CD8+ T cell as potential biomarkers of response, two groups, Pulliam and Jani et al. and Ryu et al., recently evaluated them in Merkel...

Adding a personalized neoantigen vaccine to checkpoint blockade keeps resected melanoma away in a phase IIb trial

February 7, 2024

Following surgical resection of high-risk cutaneous melanoma, patients are generally treated with checkpoint inhibitors to prevent tumor recurrence, but a high proportion of patients still recur within 5 years. In an effort to reduce these recurrence rates, Weber et al. evaluated the addition of adjuvant personalized neoantigen vaccines (mRNA-4157) in a phase IIb...

CD4+ T cells wear many hats

January 31, 2024

CD4+ T cells are best known for their roles in helping CD8+ T cells, but in recent years, researchers have identified CD4+ T cells across broad ranges of subsets playing roles in activation, recruitment, reprogramming, and direct cytotoxicicity. To better understand these CD4+ T cell roles and their contributions to antitumor immunity, Bawden...

Antitumor T cell responses detected in patients with new vaccine strategy in immune-cold tumors

January 24, 2024

Colorectal cancer (CRC) and pancreatic ductal adenocarcinoma (PDAC) have a low survival rate, low infiltration of tumor-specific tumor-infiltrating lymphocytes (TIL), infrequent neoantigen mutations, and checkpoint inhibitors are largely ineffective in PDAC and subtypes of CRC. Common mutations in the oncogenes driver KRAS (mKRAS) however can serve as immunotherapy targets. Pant et al. conducted...

You can’t kill what you can't find: dormant disseminated tumor cells (DTCs) evade T cells through “relative scarcity”

January 17, 2024

Surviving breast cancer is an incredible feat, but patients whose initial tumors are successfully cleared still face a high risk of recurrence, even years after initial treatment. Tumor recurrence can be attributed to the presence of dormant disseminated tumor cells (DTCs) that hide out in the body and can potentially seed new tumors...

No more luck of the draw: new predictive signature for efficacy PD-1 blockade

January 10, 2024

Despite its successes in some patients, immune checkpoint blockade (ICB) targeting PD-1 is not beneficial in most patients with non-small cell lung cancer (NSCLC). Determining which patients would or would not benefit from this treatment has remained a challenge. Previously, a dysfunctional T cell subset has been associated with response to treatment, but...

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