2023
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Stat5 battles Tox for epigenetic control of T cell exhaustion
December 20, 2023
In cancer immunotherapy, reversing or staving off T cell exhaustion is highly useful, and while current checkpoint blockades show substantial efficacy, they don’t appear to rewire the epigenetics that drive exhaustion in the first place. Investigating the epigenetic programming of exhaustion and potential ways to mitigate it, Beltra et al. identified Stat5 as...
New molecule targets TIL-enriched T cell subset to improve antitumor immunity
December 13, 2023
Stimulating αβ T cells through the T cell receptor (TCR) complex using CD3-agonistic antibodies as immunotherapy remains a challenge, as it activates all T cells, resulting in cytokine release syndrome and inefficient T cell activation. To overcome this issue, Hsu, Donahue, et al. designed and tested a bifunctional antibody fusion molecule fused to...
Cytokine-armed DC progenitors are an alternative to antigen-loaded DC vaccines
December 6, 2023
Using tumor antigen-loaded monocyte-derived DCs for therapeutic vaccination is a strategy that has been well explored, but with mixed clinical results. While this strategy can be effective, it is limited by the requirement for accessible tumor samples or known tumor antigens, as well as by the antigen loading process itself. To overcome these...
Activating macrophages to remodel the tumor microenvironment
November 29, 2023
One of the reasons immune checkpoint blockade (ICB) may fail in solid tumors like pancreatic ductal adenocarcinoma (PDA) is a lack of T cell infiltration and extensive myeloid inflammation in the tumor microenvironment (TME). Wattenberg et al. aimed to overcome these characteristics in recent work published in Science Immunology. Given the known plasticity...
Metabolic characteristics of DC vaccines define therapy responses
November 22, 2023
Dendritic cell (DC)-based cancer vaccines have great potential but are currently lacking in efficacy. Adamik et al. investigated the transcriptomic and immune-metabolic characteristics of DCs from patients with melanoma to better understand how cancer may impact antigen presentation function and metabolic activity of these cells. Their results were recently published in Nature Communications...
SITC - 38th Annual Meeting 2023
November 15, 2023
This week’s extensive special feature covers select talks from the SITC - 38th Annual Meeting 2023 in San Diego, CA. We have organized the content by topics below. Keynote AddressSusan Kaech Microbiome and metabolismSusan BullmanYoungseok ChoLydia Lynch Cell-based immunotherapiesFelix KorellElise WilcoxLeyuan MaKole Roybal Tumor microenvironmentRolf BrekkenBridget P. KeenanJames L. ReadingHumsa Venkatesh Cancer vaccinationAlex...
Flt3L has the opposite of a goldilocks effect thanks to two distinct DC-mediated mechanisms
November 8, 2023
Flt3L (FL) is essential for the differentiation and proliferation of classical DCs (cDCs), which play a role in recruiting various immune cell types and activating both effector and regulatory responses in cancer. Investigating the role of FL in antitumor immunity, Régnier et al. uncovered an unusual pattern, in which both high and low...
Manipulated macrophages reshape the metastatic tumor microenvironment
November 1, 2023
Liver metastases respond poorly to current immunotherapies, which may be due to the immunosuppressive tumor microenvironment (TME), and in particular, the presence of pro-tumoral tumor-associated macrophages (TAMs). To overcome this issue, Kerzel, Giacca, et al. hypothesized that enforced IFNα expression in liver metastases by genetic engineering of liver macrophages, including Kupffer cells (KCs)...
AACR Tumor Immunology and Immunotherapy Meeting 2023
October 25, 2023
This week’s extensive special feature covers select talks from the AACR Tumor Immunology and Immunotherapy Meeting 2023 in Toronto, Canada. We have organized the content by topics below. Keynote lectureCrystal Mackall T cell therapiesPhil GreenbergCarl JuneGreg Delgoffe Cytokine therapiesPablo UmanaIvana DjureticDavid Brooks Tumor immune microenvironmentCatherine J. WuThomas GajewskiPaul ThomasRobert Schreiber Immune regulationMatthew KrummelPing-Chih...
A new marching order for the T cell army in the attack of AML
October 18, 2023
Acute myeloid leukemia (AML) is the most frequent leukemia in adults. Currently, allogeneic hematopoietic stem cell transplantation, although associated with high risks for relapse, transplant-related morbidity, and graft-versus-host disease, is the only curative treatment option. At present, CAR T cell therapies targeting myeloid cell surface antigens that are overexpressed in AML, but are...
TIM-3 blockade offers new hope for incurable childhood cancer, DIPG
October 11, 2023
Mainly due to its location in the pons, a part of the brainstem that controls many of the body's vital functions, and its infiltrative nature, diffuse intrinsic pontine glioma (DIPG) is one of the most devastating and challenging childhood cancers. Currently, oncologists can only offer radiotherapy to stabilize the tumor and reduce symptoms...
Improving CAR T cell activity by removing CTLA-4
October 4, 2023
Despite major successes with CD19-directed CAR T cell therapy in various hematological malignancies, not all patients respond. Given that CAR T cells (CART) upregulate immune checkpoint molecules, and that combination treatment with immune checkpoint blockade can enhance responses, Agarwal et al. assessed whether deletion of CTLA-4 and/or PD-1 from CAR T cells could...
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...
