Weekly Digests

2021

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Chemotherapy and checkpoint inhibition differentially impact immune dynamics

October 20, 2021

While the effects of immune checkpoint blockade on the tumor microenvironment (TME) are widely investigated, the combined effect of chemotherapy and checkpoint blockade is less clear. Further, although the Impassion130 trial in advanced triple-negative breast cancer (TNBC) combining nab-paclitaxel with anti-PD-L1 therapy led to clear patient benefits and product approval, a similar trial...

When neoantigen expression is low, the T cells won’t go

October 13, 2021

In the setting of colorectal cancer (CRC), mismatch repair (MMR)-deficient or microsatellite instability (MSI)-high disease tends to have higher tumor mutation burdens (TMB) and better responses to immunotherapy than MMR-proficient and microsatellite stable (MSS) disease. However, MSS CRC still has a mutation burden that is comparable to other cancers that respond to immunotherapy...

T cells with an identity crisis: gaining NK characteristics after CMV infection

October 6, 2021

Human cytomegalovirus (HCMV) infection can have long-term immune effects, and NK and T cells both play roles in keeping HCMV latent. Based on the knowledge that CD8+ T cells can display NK cell-like properties, and that these cells can have a beneficial presence in individuals infected with particular intracellular pathogens causing tuberculosis or...

A message for macrophages: how tumors prime the pre-metastatic niche

September 29, 2021

Before cancer makes any metastatic moves, it drives the development of pre-metastatic niches in certain tissues, priming a local environment to support a future tumor. These pre-metastatic niches often contain polarized immunosuppressive macrophages; however, exactly how these macrophages acquire that phenotype is not well understood. In a recent study, Morrissey et al. explored this...

RNA to the rescue: localized cytokine delivery shapes antitumor responses

September 22, 2021

Treatment of tumors with cytokines to boost antitumor immune responses is limited in the clinic due to systemic adverse events. Intratumoral delivery of cytokines may overcome these issues and improve therapeutic efficacy. Hotz and Wagenaar et al. thoroughly investigated the efficacy of local delivery of mRNA encoding a mixture of cytokines alone or...

Dream team: TGFβ and PD-L1 targeting aligns with radiotherapy to create a beneficial immune environment

September 15, 2021

Since radiotherapy (RT) can boost immune priming, it can be a great tool to convert immune “cold” tumors into “hot” immune environments, making way for effective checkpoint inhibition therapies. However, RT may also remodel the tumor microenvironment (TME), creating barriers to immune infiltration and antitumor effects. Given that one of the main contributors...

Arming CARs with RNA to boost immune responses

September 8, 2021

Treatment of solid tumors with CAR T has various barriers to overcome to be effective. To improve efficacy, boosting the immune response by delivering pattern recognition receptor (PRR) agonists more specifically to immune than tumor cells might improve responses, given the known role of some PRRs to drive tumor progression. To do this, Johnson...

Tvax: A vaccine made from T cells

September 1, 2021

Therapeutic cancer vaccines consistently show great promise, but often fall short of expectations. Past studies have successfully used dendritic cells (DCs) to carry antigens to tumors, but DCs can be difficult to obtain and manipulate in large numbers. T cells, on the other hand, are readily available, easy to modify and expand (due...

Checkpoint inhibition clears the way for subsequent MAPK inhibition

August 25, 2021

Even though MAPK inhibitors (MAPKi, such as BRAFi or MEKi) can be an effective treatment strategy, therapy resistance limits their benefits. However, in clinical studies, patients with BRAFV600E/K metastatic melanoma, who had received prior treatment with checkpoint inhibitors, had increased efficacy of MAPKi with longer progression-free survival. Therefore, Wang, Liu, Yang, and Algazi...

Epigenetic scarring leaves T cells permanently exhausted

August 18, 2021

T cell exhaustion is accompanied by a distinct and relatively well described epigenetic state, but whether that state is reversible is not quite clear. Investigating this, Yates et al. explored the chromatin landscape of CD8+ T cells in the setting of active and cured chronic infection, and published the results in Nature Immunology...

It’s not all just PD-1: the CD155/TIGIT axis is essential for immune evasion in pancreatic cancer

August 11, 2021

Pancreatic ductal adenocarcinoma (PDAC) has a poor prognosis and is largely refractory to current clinical immunotherapies. Freed-Pastor et al. investigated the immune evasion mechanisms in this cancer type by assessing neoantigen load, neoantigen-specific T cells, and T cell characteristics, revealing a novel axis of inhibition. Their results were recently published in Cancer Cell...

Antigen specificity and phenotype of TILs

August 4, 2021

Tumor-infiltrating lymphocytes (TILs) can exhibit a variety of functional and transcriptional states, but the connection between phenotype and antigen specificity remains unclear, and decoding this relationship could provide insight into patient response to immune checkpoint blockade (ICB) therapy. With this goal in mind, Oliveira et al. and Caushi & Zhang et al. examined...

Radiotherapy from the inside out? TRT enhances immunotherapy

July 28, 2021

In the setting of cancer, radiotherapy can directly damage or kill tumor cells, and can act as an in situ vaccine that triggers antitumor immunity; the contribution of each of these mechanisms varies based on the dose. In most cases, radiation is delivered as targeted external beam radiotherapy (EBRT), but not all tumors...

A20 downregulation: a strength and a weakness for cancer

July 21, 2021

Although immune checkpoint blockade (ICB) therapy has shown impressive benefits in treating lung cancer, only a minority (~20%) of patients with non-small-cell lung cancer (NSCLC) respond to anti-PD-1/anti-PD-L1 therapy. The reasons are incompletely understood, but the tumor microenvironment and its inflammatory state could play a key role. Recently reported in Science Translational Medicine...

T<FR> are the new suppressive kids on the block for tumors

July 14, 2021

Regulatory T cells (Treg) can differentiate into follicular regulatory T cells (TFR) that have important roles in secondary lymphoid organs and may have higher suppressive activity. However, their role in antitumor immunity has not been elucidated. Eschweiler et al. investigated the role of TFR in cancer, analyzing their function, characteristics, and effects on...

In some tissues, tumors are not seen as a prime suspect

July 7, 2021

Clinically, heterogeneous immune responses have been detected between patients, between tumors in the same patient, and even by disease site. Some tumor microenvironments (TME) are typically immune cold and respond poorly to immunotherapy, such as pancreatic ductal carcinoma (PDAC). However, there are some exceptions, which provides the hope that a mechanistic understanding of...

Treg endeavors in lymph nodes and tumors

June 30, 2021

Although Tregs maintain homeostasis and fend off autoimmunity, they can also dampen the antitumor immune response. Despite these major roles, key facets of Treg biology have remained unknown. For instance, how exactly do Tregs constrain self-activated T cell activity in secondary lymphoid organs? And what regulates Treg abundance and function in the TME...

Discussion with Patrick Ott, M.D., Ph.D. about the documentary "Jim Allison: Breakthrough"

June 24, 2021

Thank you for submitting your questions and comments about the documentary Jim Allison: Breakthrough. We have answered them in this recorded video with the help of Patrick Ott, oncologist and clinical director of the Melanoma Disease Center and Center for Immuno-Oncology at the Dana-Farber Cancer Institute in Boston. BONUS: We have extended free access...

Marking a tumor for destruction with radiation

June 23, 2021

Tumors with a low mutational burden generally respond poorly to immunotherapy. Given that radiotherapy can induce mutations in tumor cells and has been found to synergize with immunotherapy, Lussier, Alspach, and Ward et al. explored whether radiation of low mutation burden tumor cells induces neoantigens that can be recognized by T cells to...

A Fountain of Youth for T cell Function

June 16, 2021

With advancing age comes a decrease in immune function, which can also dampen responses to immunotherapy. Investigating this, Nakajima et al. compared T cell subsets, based on their expression of CD44 and CD62L, in young versus aged mice. Among CD8+ T cells, CD44lowCD62Lhigh (P1) cells are defined as naive, CD44highCD62Lhigh (P2) cells are...

IL-10 rejuvenates your exhausted T cells

June 9, 2021

While immunotherapies work great in some patients, for most, results are limited. One reason for the limited therapeutic response is the induction of an “exhausted” phenotype in CD8+ TILs. Aiming to reinvigorate exhausted CD8+ TILs in the TME, Guo and Xie et al. explored the effects of IL-10 treatment and combined it with...

Anti-CD40 agonist antibodies may be the way to go for bladder cancer

June 2, 2021

When patients are diagnosed with non-muscle-invasive bladder cancer, intermediate- to high-risk patients typically undergo transurethral tumor resection, followed by intravesical treatment with Bacille Calmette-Guérin (BCG) as the standard of care. However, up to 75% of patients ultimately become unresponsive to this treatment. Even with the recent approval of anti-PD-1 therapy in the BCG-unresponsive...

New target can put the brakes on macrophage and Treg immune suppression

May 26, 2021

Given that only a subset of patients responds to current checkpoint inhibition therapies, the search for new immune checkpoint targets continues. Sharma et al. identified and investigated one such new target, LILRB4, in mouse and human tumors, and assessed the effects of blockade in a variety of mouse models. Their results were recently...

CIMT Annual Meeting 2021

May 19, 2021

Last week, the ACIR team attended the virtual 18th CIMT Annual Meeting. This week’s extensive special feature covers select talks from the conference. We are proud to recognize Takeda for sponsorship of our coverage for this conference. We have organized the content by topics below. Keynote addressUgur Sahin Tumor microenvironment and effective immunotherapySjoerd...

CD276 helps cancer stem cells dodge the immune bullet

May 12, 2021

Cancer stem cells (CSCs) are considered the “seeds” of tumor metastasis, but how these cells escape the effects of chemotherapy and immune surveillance is unclear. Wang et al. previously detected CSCs with a limited expression of PD-L1 in head and neck squamous cell carcinoma (HNSCC). In an attempt to detect other targetable checkpoints...

What drives glycolysis in tumors, and how to stop it

May 5, 2021

In an effort to investigate epigenetic mechanisms that contribute to tumor immune evasion, Liu, Liang, Xu, Dong, and Dong et al. recently explored the connection between the RNA demethylase FTO, increased glycolysis in tumor cells, and reduced T cell activation in the tumor microenvironment. Further, the researchers developed and tested a potential strategy...

Making the cut: exitrons as a new source of neoantigens

April 28, 2021

Exitrons are internal regions of an exon that have both protein-coding and splicing potential. When these exitrons are spliced, it may lead to protein isoforms, including in-frame deletions, as well as out-of-frame neo open reading frames. As not much is known about the abundance or impact of exitrons in cancer, Wang and Liu...

AACR Annual Meeting 2021

April 21, 2021

Last week, the ACIR team attended the virtual AACR Annual Meeting 2021. This week’s extensive special feature covers select talks from the conference. We have organized the content by topics below. Tumor microenvironment and effective immunotherapySergio QuezadaTheresa KolbenAntoni RibasIra Mellman Combination therapiesTaha MerghoubGeorge Coukos T cell dysfunction and exhaustionE. John WherryAndrea SchietingerDaniela Stefanie...

DCs can TAP out of ordinary cross-presentation

April 14, 2021

Our classic understanding of antigen presentation to CD8+ T cells involves transport of cytosolic peptides into the endoplasmic reticulum (ER) by the transporter associated with antigen processing (TAP), where they can be loaded onto MHC class I molecules through the canonical peptide loading complex. Cross-presentation occurs when extracellular antigens are presented on MHC-I...

Lymphangiogenesis gets vaccine responses back on track

April 7, 2021

Lymphangiogenesis, the growth of lymphatic vessels, has contradictory consequences in cancer; within the tumor, it is associated with metastasis and poor prognosis, but outside of the tumor, it can boost T cell immunity. Using this knowledge, Sasso et al. developed a cancer vaccine strategy to increase tumor control and immune memory. The preclinical...

How do we improve DC vaccines? Let us count the ways.

March 31, 2021

In previous arms of a sequential, multi-arm, ovarian cancer clinical trial, Tanyi and Chiang et al. showed that the use of a dendritic cell vaccine consisting of DCs pulsed with oxidized autologous whole tumor lysate (OCDC) can elicit T cell responses to tumor-associated antigens and neoantigens. They also showed that the addition of Bevacizumab...

TIL going viral: detection of TCR cross-specificity for viral and tumor antigens

March 24, 2021

Virus-specific tumor-infiltrating T cells have previously been considered bystander cells not contributing to the antitumor response in the same way that T cells specific to tumor-associated antigens (TAAs) might. To begin to unpack the vast amount of TCR sequence data available from tumor and normal tissue samples, Chiou and Tseng et al. used...

T cells and myeloid cells may be in a “dysfunctional” friendship

March 17, 2021

The role of the tumor immune microenvironment (TME) in tumor progression is increasingly appreciated, but for certain cancers, our understanding remains incomplete. Recently, single-cell analysis techniques have enabled comprehensive analysis and supported our knowledge of tumor development and treatment response. Now published in Cancer Cell, Braun and Street et al. used single-cell RNA...

Defining CD4+ T cells with a license to kill

March 10, 2021

The helper function of CD4+ T cells in antitumor immune responses has been characterized, but much less is known about the role of cytotoxic CD4+ Th cells (Th-CTX) in tumors. Cachot, Bilous, and Liu et al. investigated the presence, phenotype, and cytolytic function of tumor-specific Th-CTX using single-cell transcriptomics, peptide–MHC-II multimers, and a...

Epitope spreading is spreading success in immunotherapy

March 3, 2021

Successful immune checkpoint blockade in patients with melanoma is often associated with a high mutational burden, a high level of predicted neoantigens, and an interesting side effect – vitiligo. In a study recently published in Science Translational Medicine, Lo et al. investigated whether vitiligo, an autoimmune reaction against melanocytes, contributes to the efficacy...

Tumors don’t want an invite to the TCR-T cell party

February 24, 2021

Given that it is consistently expressed by tumor cells and contributes to malignant transformation, the HPV E7 antigen is an interesting target for immunotherapy in HPV-associated carcinomas. Nagarsheth et al. previously developed a high avidity TCR that recognizes the E711-19 antigen complexed with HLA-A*02:01. The TCR-T cells containing this E7-targeting TCR were assessed...

Trust a first responder’s gut

February 17, 2021

A growing understanding of the gut microbiome has uncovered critical roles in regulating host immunity, metabolic health, and progression of diseases such as cancer. Recently, the composition of the microbiome has been linked to anti-PD-1 therapeutic response. Fecal microbiota transplant (FMT), in which favorable bacterial species (in this case, those conducive to anti-PD-...

Multiple routes lead to Rome: new insights in TIL origins

February 10, 2021

Even though TILs predict survival and response to immune checkpoint inhibition in non-small cell lung cancer (NSCLC), the origins of these cells remain largely unknown. Gueguen and Metoikidou et al. performed single-cell RNAseq (scRNAseq) and TCRseq (scTCRseq) on tumors, healthy adjacent tissue (juxtatumor), and peripheral blood to investigate CD8+ TIL differentiation and origin...

NeoVax: A Long-Term Follow-up

February 3, 2021

“Durable immunity is a hallmark of successful vaccination,” according to Hu, Leet, and Allesøe et al. in a paper published in Nature Medicine. The team of researchers recently followed up on the long-term effects of vaccination with NeoVax, a long-peptide vaccine that targets up to 20 personal neoantigens per patient. Their recent data extends...

Checkpoint receptors - unexpectedly essential for forming memory T cells

January 27, 2021

Even though the importance of forming long-lived memory CD8+ T cells is widely acknowledged, the origin of this T cell subset remains largely unknown. Johnnidis and Muroyama et al. used a well established viral infection model to phenotype and functionally characterize the cell subsets responsible for memory formation and recall responses, and uncovered...

Make it a double: bispecific antibodies targeting PD-1 and CTLA-4

January 20, 2021

Dual blockade of PD-1 and CTLA-4 checkpoint molecules using monoclonal antibodies has taken advantage of their distinct and complementary mechanisms to enhance clinical responses over monotherapies. However, many patients still fail to respond, and over half of patients experience severe treatment-related adverse events. To improve upon these outcomes, researchers have investigated bispecific targeting...

Focus on suppressive macrophages may boost effects of PARP inhibitors

January 13, 2021

Even though FDA-approved poly(ADP-ribose) polymerase inhibition (PARPi) can be very effective in BRCA-mutant breast cancer, responses are not durable, prompting a need for combination therapies. To provide a mechanistic basis for considering immunotherapeutic strategies, Mehta et al. used high-dimensional single-cell and multi-omics profiling in patient samples and in mouse models to study changes...

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