Weekly Digests

2023

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Exhausted but still active: subpopulation of TIL responds to anti-PD-1 in HNSCC

September 27, 2023

Immune checkpoint blockade (ICB) targeting PD-1 is increasingly used as neoadjuvant therapy. However, the mechanisms and cell types determining ICB responses remain poorly understood. Oliveira, Egloff, Afeyan, et al. compared T cell activation status and dynamics in responders and non-responders to neoadjuvant pembrolizumab in patients with head and neck squamous cell carcinoma (HNSCC)...

Better together: Vaccination with linked CD4+ and CD8+ T cell neoantigens synergizes with anti-PD-1

September 20, 2023

Neoantigen vaccination and immune checkpoint blockade (ICB) are both strategies that can be employed to enhance antitumor T cell responses, but both are often met with resistance, and their use in combination has not been fully explored. Investigating these strategies in tumors with low mutation burdens, Dolina et al. found that immunization with...

Overcoming toxicity of pan-hematological CAR-T with epitope editing

September 13, 2023

CAR T cell therapy for hematological cancers can be highly effective, but is currently limited to antigens that are only expressed by tumor cells or by lineages that are non-essential. Targeting antigens expressed by all tumor cells is often associated with on-target/off-tumor toxicities to normal hematopoietic cells. Two recent papers used epitope editing...

RIGging up extracellular vesicles for antitumor immunity

September 6, 2023

As a form of communication/signaling, cells frequently release extracellular vesicles (EVs). While EVs released by cancer cells have previously been associated with immune evasion and cancer progression, they can also potentially carry tumor antigens and stimulate immune responses. Investigating the mechanisms that govern cancer EV biogenesis, cargo, and functions, Heidegger and Stritzke et...

IL-2 therapy requires IL-Rα binding to stimulate tumor-specific immune responses

August 30, 2023

Recent advances in IL-2 treatment strategies have led to the development of IL-2Rβγ-biased approaches in which toxicity is expected to be lower. However, recent clinical research has shown disappointing results. Wu, Chia, et al. assessed the mode of action of various IL-2 constructs to help the future design of IL-2 treatments. Their results...

Failing fast: CD8+ T cell dysfunction programming is induced early in tumors

August 16, 2023

Tumor-specific CD8+ T cells can be strong effectors in the immune battle against cancer, but they are often limited by dysfunction/exhaustion induced by the tumor microenvironment. Rudloff et al. investigated this dysfunction by comparing differentiation, cell division, and chromatin accessibility in antigen-specific CD8+ T cells in tumor versus acute infection models. This revealed...

New insights on the mechanism of action of anti-CTLA-4 immune checkpoint blockade

August 9, 2023

The mechanism of action of anti-CTLA-4 therapy remains incompletely understood. Hypotheses suggest that either antagonism of CTLA-4:B7 binding or Fc effector-mediated regulatory T cell (Treg) depletion might be responsible for the efficacy of the therapy. Lax et al. researched both these mechanisms with engineered antibodies, allowing testing of separate and combined antagonism and...

IL-7R(hi) CD8+ T cells keep cancer from making a comeback

August 2, 2023

Melanomas are often immunogenic and responsive to surgical resection and checkpoint blockade therapies; however, tumor recurrence is still a common problem. To better understand and ultimately prevent tumor recurrence, Micevic and Daniels et al. recently identified a population of L-7Rhi CD8+ T cells that is mostly tumor-specific, is maintained in lymph nodes long-term...

Turning the tide: reprogrammed tumor cells become APCs

July 26, 2023

One immune evasion mechanism that limits antitumor immunity and response to immunotherapy is the downregulation of antigen processing and presentation in tumors. Zimmermannova and Ferreira et al. aimed to reverse this mechanism by forced expression of dendritic cell transcription factors in tumor cells to induce an antigen-presenting cell (APC) phenotype. Their results were...

Neoantigen-specific CD4+ T cells are powerful helpers

July 19, 2023

CD4+ T cells have been shown time and time again to play roles in antitumor immunity, but the exact mechanism and factors that influence their effects remain unclear. Previous research in mice identified a specific CD4+ T cell response to CLTCH129>Q – a validated neoantigen target expressed by the MHC-II-deficient squamous cell carcinoma...

Novel CD40 agonistic antibodies with immune activating antitumor effects

July 12, 2023

CD40 expressed on antigen-presenting cells (APCs) regulates immune responses by binding to CD40L on T cells, which stimulates antigen presentation and activation of both cell subsets. Therefore, targeting CD40 with an agonist antibody has potential as an immunotherapy for cancer. Current research into CD40 agonistic antibodies is focused on increasing efficacy and reducing...

CXCR3 on Tregs controls their accumulation, activation

July 5, 2023

Regulatory T cells (Tregs) often present a challenge to antitumor immunity, but exactly how they suppress immune responses is not entirely understood. Investigating the accumulation and activation of Tregs in tumors, Moreno Ayala et al. found that CXCR3+ Tregs interacted preferentially with CXCL9+ DC1s in tumors, and that genetic knockout of CXCR3 specifically...

A few CD4+ T cells go a long way against immune-evasive tumors

June 28, 2023

Investigating the contributions of CD4+ T cells to antitumor immunity, Kruse, Buzzai, Shridhar, and Braun et al. unraveled a mechanism through which a small number of CD4+ T cells can eradicate MHC-deficient, IFNγ-unresponsive tumors that escape direct CD8+ T cell targeting. Their results, recently published in Nature, show that, in concert with innate...

New gut-associated checkpoint might be involved in ICB resistance in cancer

June 21, 2023

In several cancer types, antibiotics limit the efficacy of immune checkpoint blockade (ICB) therapy. On the other hand, metastatic colorectal cancer (CRC) is largely resistant to ICB. The mechanisms behind these effects remain largely unknown. Two recent publications suggest that a novel checkpoint axis, the mucosal addressin cell adhesion molecule 1 (MAdCAM-1)-α4β7 integrin...

CD4+ CAR T cells kill tumor cells from a distance with IFNγ

June 14, 2023

CD8+ T cells often take center stage when it comes to immunotherapy, but in some cases, CD4+ T cells contribute strongly, and may even exert more potent effects than CD8+ T cells. Investigating the variable contributions of CD4+ T cells to antitumor efficacy in CAR T cell therapy, Boulch et al. explored the...

A new combination for fighting gliomas in both mice and patients

June 7, 2023

In the hunt for treatments against recurrent glioblastoma, one option that has shown efficacy in mouse models is L19TNF, an antibody–cytokine fusion molecule that targets the EDB domain of fibronectin, which is highly expressed in blood vessels in glioblastoma (but not normal blood vessels), and delivers TNF, which increases the permeability of newly...

Personalized PDAC vaccines have entered the clinic

May 31, 2023

Pancreatic ductal adenocarcinoma (PDAC) is a leading cause of cancer death, and while surgery can be curative, the vast majority of patients relapse and succumb to their disease, even when given additional chemotherapy. While PDAC is generally resistant to immune checkpoint inhibitors, recent studies have shown that they do often harbor immunogenic neoantigens...

Targeting NRP2-VEGF to overcome immunosuppression and chemotherapy resistance in aggressive cancers

May 24, 2023

Neuropilin-2 (NRP2) is a transmembrane protein that binds ligands such as vascular endothelial growth factor (VEGF). It is expressed in several tumor types, and overexpressed in aggressive, treatment-resistant tumors, such as triple-negative breast cancer (TNBC), metastatic castration-resistant prostate cancer (mCRPC), and neuroendocrine prostate cancer (NEPC). Two recent papers from the same laboratory, published...

CIMT Annual Meeting 2023

May 17, 2023

The ACIR team attended the CIMT Annual Meeting 2023 in Mainz, Germany. This week’s extensive special feature covers select talks from the conference. We have organized the content by topics below. Tumor immune microenvironment and implications for immunotherapyGuoliang CuiRafi AhmedMiriam Merad Ira Mellman Judit Díaz-Gómez Naveen MehtaT cell therapies and bispecificsGeorge Coukos Kristen...

Tumor-reactive T cells engineered to not get exhausted after adoptive transfer

May 10, 2023

T cell exhaustion in response to chronic activation of effector CD8+ T cells limits the efficacy of particular adoptive cell transfer (ACT) therapies. Corria-Osora et al. hypothesized that T cells could be rewired by engineering them to express orthogonal cytokines to acquire and maintain a functional state upon chronic stimulation. The researchers assessed...

Targeting Tregs, but only in the tumor

May 3, 2023

Tregs are an attractive target in cancer immunotherapy, as they play a strong role in inhibiting antitumor immune responses. However, targeting Tregs can also disrupt the system of checks and balances that prevents harmful autoimmune responses. In search of strategies for targeting Tregs that infiltrate tumors (TI-Tregs) without disrupting Tregs in the periphery...

AACR Annual Meeting 2023

April 26, 2023

Last week, the ACIR team attended the AACR Annual Meeting 2023 in Orlando, Florida. This week’s extensive special feature covers select talks from the conference. We have organized the content by topics below. Personalized cancer vaccinesJeffrey S. WeberVinod P. BalachandranCatherine J. Wu Tumor immune microenvironment and beyondGabriel A. RabinovichIgnacio MeleroKarin E. de VisserFlorencia...

NKp46 finds its ligand in ecto-CRT on stressed and senescent cells

April 19, 2023

Natural killer (NK) cells are known for their ability to recognize and kill targets that are transformed, infected, stressed out, or senescent, and while NK cells are known to act through several NK cell receptors, many of the ligands that activate those receptors have remained elusive. In a recent study published in Nature...

Masking bispecific T cell engagers until they reach the tumor improves their toxicity profile

April 12, 2023

Bispecific T cell engagers (TCE) targeting tumor-associated antigens (TAA) that are expressed at low levels in healthy tissues can cause significant toxicity due to on-target, off-tumor immune effects. To overcome this issue, Cattaruzza et al. developed a protease-releasable masking technology that allows for the creation of precision-activated TCEs (XPAT proteins) that are unmasked...

Neutrophils help to clear including antigen escape variants in tumors

April 5, 2023

In a previous study, the combination of cyclophosphamide (CTX), CD4+ T cells specific for the melanoma antigen Trp1 (Trp1 T cells), and an anti-OX40 agonist antibody cleared advanced mouse melanoma tumors, including tumor cells that did not express the Trp1 target antigen. Investigating this interesting phenomenon, Hirschhorn et al. found that while T...

Predicting immunotherapy responses using circulating tumor DNA

March 29, 2023

It remains a challenge to determine which patients might benefit from immunotherapy, and in drug trials, early endpoints, such as progression-free survival (PFS) and overall response rates, may not correspond with overall survival (OS). Therefore, trials may take many years to conduct to show a benefit in OS. Looking into other early measures...

Tumor PD-L1 promotes metastasis through a myeloid middle man

March 22, 2023

PD-L1 on tumors (tPD-L1) is a well known antagonist of antitumor immune responses, and a biomarker of improved clinical outcomes and survival following PD-1/PD-L1 checkpoint blockade. However, recent research has shown that PD-L1 on other immune cells in the tumor microenvironment may be responsible for suppressing cytotoxic T cells. Taking another look at...

Turning tumor cells against themselves as a new vaccination approach

March 15, 2023

A major challenge for cancer vaccination is the choice of which tumor-associated antigens (TAAs) to target to elicit tumor-specific T cell responses, given the large tumor heterogeneity. To overcome this issue, Linde et al. developed a cancer vaccination approach in which cancer cells are reprogrammed into myeloid lineage cells, which are phagocytic and...

Targeting type 1 NKT and Vγ9Vδ2-T cells with a bsTCE

March 8, 2023

Bispecific T cell engagers (bsTCE) are powerful immunotherapeutic tools, but they come with issues of toxicity and Treg activation. In an effort to overcome some of these challenges, Lameris et al. developed a CD1d-Vδ2 bsTCE to activate both type 1 NKT cells and Vγ9Vδ2-T cells against cancers expressing CD1d – a non-polymorphic MHC-I-like...

CD5 on DCs brings antitumor T cell responses to life

March 1, 2023

To induce effective antitumor T cell responses in response to immune checkpoint blockade (ICB) treatment, effective priming by dendritic cells (DCs) is essential. However, the characteristics of effective DC responses during ICB remain largely unclear. Having previously shown that migratory CD5+ DCs in the skin can prime CD4+ and CD8+ T cells more...

Improving D2C7-immunotoxin therapy with agonist CD40

February 22, 2023

Glioblastomas (GBMs) are highly intracranially invasive and resistant to immunotherapy. In a recent phase 1 clinical trial, researchers evaluated D2C7 – an immunotoxin consisting of Pseudomonas exotoxin A and a recombinant antibody fragment that targets wild-type EGFR (EGFRwt) and mutant EGFR variant III (EGFRvIII) proteins present in GBM – in patients with recurrent...

New source of tumor antigens found that is targetable with immunotherapy

February 15, 2023

Epigenetic alterations, such as the derepression of transposable elements (TEs), are common events in cancer. Two recent papers from Amigorena and colleagues published in Science Immunology investigated whether non-canonical splice junctions between exons and TEs may serve as a source of tumor antigens in murine models and patient samples. To identify non-canonical splicing...

Location, location, location: why lung tumors trigger weak immune responses in mice

February 8, 2023

In an effort to better understand why mice mount weaker immune responses to tumors in the lungs than to those in the flank, Zagorulya et al. compared immune priming in their respective tumor-draining lymph nodes: the mediastinal lymph node (mLN) and the inguinal lymph node (iLN). As they unraveled this mechanism underlying these...

Interferon signaling can be too much of a good thing in the immunotherapy setting

February 1, 2023

Despite the important role that Type I (IFNα and β) and Type II (IFNγ) interferons have in antitumor immunity, both by upregulating HLA in cancer cells and activating T cells, prolonged IFN signaling can be pro-tumorigenic and has been associated with immunotherapy resistance. Therefore, Qiu and Xu et al. investigated whether interfering with...

Agonistic anti-PD-1 antibodies turn on the immunosuppressive activity of PD-1

January 25, 2023

Antibodies blocking the PD-1/PD-L1 interaction are widely used to enhance immune responses against cancer. This group of antibodies binds to the membrane-distal region of the PD-1 molecule. In a recent paper published in Science Immunology, Suzuki and Tajima et al. identified another group of anti-PD-1 antibodies recognizing the membrane-proximal extracellular region of PD-1...

Checkpoint blockade to overcome acquired resistance to immunocytokine

January 18, 2023

The immunocytokine PD1-IL2v, a fusion of an anti-PD-1 antibody with an IL-2 variant that does not stimulate Treg responses, has been developed to target activation of CD8+ T cells in the tumor via PD-1 binding. Tichet and Wullschleger et al. investigated mechanisms behind intrinsic and adaptive resistance to this type of therapy in...

IL-6 blockade could enhance PD-L1 immunotherapy

January 11, 2023

In a search for potential drivers of resistance to anti-PD-L1 immunotherapy, Huseni, Wang, Klementowicz, and Yuen et al. identified IL-6 as a correlate of poor response across various tumor types in large clinical trials. To better understand how IL-6 impacts tumor control and responses to immunotherapy, the researchers analyzed several sources of clinical...

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