Radiation therapy as a biological modifier of the breast cancer immune microenvironment.

Radiotherapy has attracted considerable attention as a means to alter the immune cell compartment of breast malignancies in support of increased sensitivity to immunotherapy. Recent data from Schalck and colleagues corroborate the notion that dose is a critical determinant of the immunological effects of radiotherapy on the tumor microenvironment.

Epigenetic regulation of cancer stemness.

Gene expression is finely controlled by the abundance and activation status of transcription factors and their regulators, as well as by a number of reversible modifications of DNA and histones that are commonly referred to as epigenetic marks. Such alterations (i.e.

An immunological mechanism of resistance to CDK4/6 inhibitors in HR breast cancer.

CDK4/6 inhibitors are central to the clinical management of HRHER2 breast cancer. We have recently demonstrated that immunosuppressive, IL17-secreting γδ T cells recruited to the tumor microenvironment by a CCL2-dependent mechanism upon CDK4/6 inhibition can repolarize tumor-associated macrophages toward a CX3CR1 phenotype associated with resistance to therapy.

The microbiota in radiotherapy-induced cancer immunosurveillance.

Radiotherapy has an established role in the clinical treatment of patients with a variety of cancers owing to the ability to preferentially kill malignant cells mostly while sparing their non-malignant counterparts. Results from phase I-II trials also suggest that radiotherapy can have therapeutically relevant immunostimulatory effects, especially when combined with immune-checkpoint inhibitors. Over the past two decades, evidence has emerged showing that intestinal microbial communities have a major influence on the immunological tonus of patients with cancer and can influence sensitivity to various immunotherapies, including immune-checkpoint inhibitors and chimeric antigen receptor T cells.

IL-17A-secreting γδ T cells promote resistance to CDK4/CDK6 inhibitors in HRHER2 breast cancer via CX3CR1 macrophages.

Resistance to cyclin-dependent kinase 4/6 (CDK4/CDK6) inhibitors leads to treatment failure and disease progression in women with hormone receptorHER2 (HRHER2) breast cancer (BC). We delineated a hypoxia-sensitive, CCL2-dependent pathway recruiting interleukin-17A (IL-17A)-secreting γδ T cells to mouse HRHER2 BCs following CDK4/CDK6 inhibition, resulting in repolarization of tumor-associated macrophages (TAMs) toward an immunosuppressive CX3CR1 phenotype associated with resistance. Increased IL-17A signaling and intratumoral γδ T cell abundance positively correlated with advanced grade and/or reduced survival in two cohorts of individuals with HRHER2 BC.

mtDNA transfer from senescent cancer cells to MDSCs promotes immunosuppression.

Sublethal apoptotic stress causing the permeabilization of some mitochondria coupled with cytosolic mitochondrial DNA (mtDNA) accumulation is known to promote cellular senescence. Lai et al. have recently demonstrated that this may be accompanied by mtDNA release within extracellular vesicles that promote local immunosuppression via myeloid-derived suppressor cells.

Regulation of inflammatory processes by caspases.

Historically, mammalian caspases (a group of cysteine proteases) have been catalogued into two main families based on major biological function: inflammatory caspases and apoptotic caspases. Accumulating evidence from preclinical models, however, argues against such a clearcut distinction, for two main reasons. First, at least in mammals, apoptotic caspases are generally dispensable for cells to succumb to apoptotic stimuli but instead regulate the kinetic and microenvironmental manifestations of the cellular demise in the context of a complex interplay with other cell death pathways.

Spatial transcriptomic analysis of immune checkpoint blockade response in triple negative breast cancers with tertiary lymphoid structures.

Tertiary lymphoid structures (TLSs) are associated with improved cancer immunotherapy responses. However, TLSs vary in their ability to elicit anticancer immune activity, so it is important to develop databases that allow study of variables that regulate their function. We applied single RNA molecule resolution imaging to longitudinal biopsies taken from women with TLS-enriched triple negative breast cancers prior to therapy, after pembrolizumab and after pembrolizumab plus radiation therapy.

Molecular mechanisms of immune cell death in immunosenescence.

Along with organismal aging, multiple compartments of the immune system undergo a progressive functional degeneration that may contribute to - or at least allow for - disease, a scenario that is commonly known as "immunosenescence". While not all immune cell populations suffer from organismal aging through similar mechanisms, immunosenescence appears to involve numerical alterations in specific immune cell types that - at least in some settings - result from the unscheduled activation of regulated cell death (RCD), often along with unbalanced hematopoietic output downstream of thymic involution and bone marrow defects. Here, we critically discuss core RCD mechanisms including apoptosis, necroptosis, ferroptosis, pyroptosis and NETosis as key regulators of global immune homeostasis in the context of immunosenescence.

CYPD limits HR mammary carcinogenesis in mice.

Mitochondrial permeability transition (MPT)-driven necrosis and necroptosis are regulated variants of cell death that can drive inflammation or even promote antigen-specific immune responses. In oncological settings, indolent inflammatory reactions have been consistently associated with accelerated disease progression and resistance to treatment. Conversely, adaptive immune responses specific for tumor-associated antigens are generally restraining tumor development and contribute to treatment sensitivity.

Metabolic switches in cell death regulation.

The death of mammalian cells is generally regulated by a complex interplay amongst distinct molecular machineries that ultimately determines the kinetic and immunological consequences of the process. Recent data from Song et al. delineate a new metabolic circuitry through which apoptotic signals may actively suppress cell death via ferroptosis.

Updates on radiotherapy-immunotherapy combinations: Proceedings of 8th Annual ImmunoRad Conference.

The annual ImmunoRad Conference has established itself as a recurrent occasion to explore the possibility of combining radiation therapy (RT) and immunotherapy (IT) for clinical cancer management. Bringing together a number of preclinical and clinical leaders in the fields of radiation oncology, immuno-oncology and IT, this annual event fosters indeed essential conversations and fruitful exchanges on how to address existing challenges to expand the therapeutic value of RT-IT combinations. The 8th edition of the ImmunoRad Conference, which has been held in October 2024 at the Weill Cornell Medical College of New York City, highlighted exciting preclinical and clinical advances at the interface between RT and IT, setting the stage for extra progress toward extended benefits for patients with an increasing variety of tumor types.

Partial mitochondrial involvement in the antiproliferative and immunostimulatory effects of PT-112.

PT-112 is a novel small molecule exhibiting promising clinical activity in patients with solid tumors. PT-112 kills malignant cells by inhibiting ribosome biogenesis while promoting the emission of immunostimulatory signals. Accordingly, PT-112 is an authentic immunogenic cell death (ICD) inducer and synergizes with immune checkpoint inhibitors in preclinical models of mammary and colorectal carcinoma.

The cold immunological landscape of ATM-deficient cancers.

Background: Mutations in genes encoding DNA repair factors, which facilitate mismatch repair, homologous recombination, or DNA polymerase functions, are known to enhance tumor immunogenicity. Ataxia telangiectasia mutated () is a central regulator of DNA double-strand break repair and is frequently affected by somatic or germline mutations in various cancer types, including breast, prostate, pancreatic, and lung cancer. However, the consequences of loss on tumor immunogenicity are poorly understood.

Impact of radiation therapy on the immunological tumor microenvironment.

External beam radiation therapy (RT) is a cornerstone of modern cancer management, being utilized in both curative and palliative settings due to its safety, efficacy, and widespread availability. A primary biological effect of RT is DNA damage, which leads to significant cytostatic and cytotoxic effects. Importantly, malignant cells possess a limited capacity for DNA repair compared to normal cells, and when combined with irradiation techniques that minimize damage to healthy tissues, this creates an advantageous therapeutic window.

A macrophage-neutrophil program drives mammary carcinogenesis.

The molecular and cellular pathways through which breast cancer evades immunosurveillance remain poorly understood. Recent data from Camargo et al. demonstrate that - on recruitment to the tumor microenvironment by ductal macrophages - a heterogeneous population of neutrophils can establish physical contacts with malignant cells within spatial niches that sustain mammary oncogenesis.

The diversity of CD8 T cell dysfunction in cancer and viral infection.

CD8 T cells that are repeatedly exposed to antigenic stimulation, such as in the context of progressing neoplasms and chronic viral infections, acquire a dysfunctional or hypofunctional state that is generally known as exhaustion. There have been considerable efforts to develop therapeutic strategies that prevent exhaustion in these pathological scenarios, but there has been limited success. This may be because exhaustion is not the only source of T cell hypofunction in cancer and chronic viral infection.

Total body irradiation primes CD19-directed CAR T cells against large B-cell lymphoma.

CD19-targeting chimeric antigen receptor T cells (CART19) have demonstrated significant effectiveness in treating relapsed or refractory large B-cell lymphoma (LBCL). However, they often fail to sustain durable remissions in more than half of all treated patients. Therefore, there is an urgent need to identify approaches to enhance CART19 efficacy.

Low-dose irradiation of the gut improves the efficacy of PD-L1 blockade in metastatic cancer patients.

The mechanisms governing the abscopal effects of local radiotherapy in cancer patients remain an open conundrum. Here, we show that off-target intestinal low-dose irradiation (ILDR) increases the clinical benefits of immune checkpoint inhibitors or chemotherapy in eight retrospective cohorts of cancer patients and in tumor-bearing mice. The abscopal effects of ILDR depend on dosimetry (≥1 and ≤3 Gy) and on the metabolic and immune host-microbiota interaction at baseline allowing CD8 T cell activation without exhaustion.

Proceedings of the National Cancer Institute Workshop on combining immunotherapy with radiotherapy: challenges and opportunities for clinical translation.

Radiotherapy both promotes and antagonises tumour immune recognition. Some clinical studies show improved patient outcomes when immunotherapies are integrated with radiotherapy. Safe, greater than additive, clinical response to the combination is limited to a subset of patients, however, and how radiotherapy can best be combined with immunotherapies remains unclear.