The role of regulatory T cells in the response to radiation therapy in head and neck cancer (original) (raw)

Ionizing radiation sensitizes tumors to PD-L1 immune checkpoint blockade in orthotopic murine head and neck squamous cell carcinoma

OncoImmunology

Immunotherapy clinical trials targeting the programmed-death ligand axis (PD-1/PD-L1) show that most head and neck squamous cell carcinoma (HNSCC) patients are resistant to PD-1/PD-L1 inhibition. We investigated whether local radiation to the tumor can transform the immune landscape and render poorly immunogenic HNSCC tumors sensitive to PD-L1 inhibition. We used the first novel orthotopic model of HNSCC with genetically distinct murine cell lines. Tumors were resistant to PD-L1 checkpoint blockade, harbored minimal PD-L1 expression and tumor infiltrating lymphocytes at baseline, and were resistant to radiotherapy. The combination of radiation and PD-L1 inhibition significantly enhanced tumor control and improved survival. This was mediated in part through upregulation of PD-L1 on tumor cells and increased T-cell infiltration after RT, resulting in a highly inflamed tumor. Depletion of both CD4 and CD8 T-cells completely abrogated the effect of anti PD-L1 with radiation on tumor growth. Our findings provide evidence that radiation to the tumor can induce sensitivity to PD-L1 checkpoint blockade in orthotopic models of HNSCC. These findings have direct relevance to high risk HNSCC patients with poorly immunogenic tumors and who may benefit from combined radiation and checkpoint blockade.

Synergies Radiotherapy-Immunotherapy in Head and Neck Cancers. A New Concept for Radiotherapy Target Volumes—“Immunological Dose Painting”

Medicina, 2020

The combination of immune checkpoint inhibitors and definitive radiotherapy is investigated for the multimodal treatment of cisplatin non-eligible locally advanced head and neck cancers (HNC). In the case of recurrent and metastatic HNC, immunotherapy has shown benefit over the EXTREME protocol, being already considered the standard treatment. One of the biggest challenges of multimodal treatment is to establish the optimal therapy sequence so that the synergistic effect is maximal. Thus, superior results were obtained for the administration of anti-CTLA4 immunotherapy followed by hypofractionated radiotherapy, but the anti-PD-L1 therapy demonstrates the maximum potential of radio-sensitization of the tumor in case of concurrent administration. The synergistic effect of radiotherapy–immunotherapy (RT–IT) has been demonstrated in clinical practice, with an overall response rate of about 18% for HNC. Given the demonstrated potential of radiotherapy to activate the immune system throug...

Radiochemotherapy induces a favourable tumour infiltrating inflammatory cell profile in head and neck cancer

Oral Oncology, 2012

Head and neck squamous cell cancers (HNSSC) generate an immune-suppressive micro-environment by a specific pattern of tumour infiltrating inflammatory cells. The aim of our study was to evaluate the impact of radiochemotherapy on the numbers and composition of inflammatory cells and its influence on outcome. Fifty-eight patients suffering from oral cavity cancer were studied, whose therapy consisted of concurrent radiochemotherapy followed by surgery. Numbers and ratios of tumour infiltrating inflammatory cells were compared prior to and after radiochemotherapy. Intraepithelial and stromal location of tumour infiltrating inflammatory cells was analysed separately. Infiltration of CD3 + , CD4 + , CD25 + , FoxP3 + , CD8 + , Granzyme B + , CD20 + and CD68 + cells predominated in the peritumoural stromal compartment, whereas CD1a + dendritic cells were found more frequently in the intraepithelial compartment. Neoadjuvant treatment was associated with a general decrease of tumour infiltrating inflammatory cells in both compartments. The CD8 + and Granzyme B + cytotoxic cells decreased only slightly after RCT. In contrast, the decrease of FoxP3 + regulatory T cells was more pronounced and the cytotoxic T-cell/FoxP3 + ratio increased 2-to 3-fold in both compartments, respectively. Patients with high cytotoxic cell numbers, high dendritic cell numbers and a high ratio of cytotoxic cells to regulatory T cells had a better disease free survival. Concurrent radiochemotherapy of oral squamous cell carcinoma was shown to drive the composition of inflammatory cells in a direction which is supposed to be prognostically favourable.

Role of T lymphocytes in tumor response to radiotherapy

Frontiers in Oncology, 2012

Over thirty years ago, Helen Stone and colleagues compared the effects of local tumor irradiation in immunocompetent and T cell deficient mice, providing the first evidence that tumor response to radiotherapy is impaired in the absence of a normal T cell repertoire. In the following three decades there has been an exponential growth in understanding T cells and the complex molecular mechanisms that regulate their activation, migration to tumors and effector functions. We now also know that tumor progression is intrinsically linked to the development of multiple immunosuppressive mechanisms that allow cancer cells to escape immune control. Recent evidence about the role of T cells in determining the prognosis and outcome of patients at any clinical stages of cancer has been instrumental in re-directing the concept of immunosurveillance and immunoediting from the realm of preclinical models to the reality of clinical observations. Importantly, cell death induced by standard anti-cancer therapies like chemotherapy and radiation has been demonstrated to involve the immune system and, in certain specific settings, enable a specific immune response. It is, therefore, not surprising that the last few years have seen an increase in investigations exploring how to harness the ability of radiation to induce anti-tumor immune responses. We will review here the experimental evidence that anti-tumor T cells are key players in tumor control achieved by radiotherapy. The effects of radiation on the tumor that have been shown to enhance the priming and effector phases of anti-tumor immunity will be discussed. Finally, we will highlight promising combinations of immune response modifiers that enhance T cell function with radiotherapy which are being tested in the clinic.

Overcoming Resistance to Combination Radiation-Immunotherapy: A Focus on Contributing Pathways Within the Tumor Microenvironment

Frontiers in Immunology

Radiation therapy has been used for many years to treat tumors based on its DNA-damage-mediated ability to kill cells. More recently, RT has been shown to exert beneficial modulatory effects on immune responses, such as triggering immunogenic cell death, enhancing antigen presentation, and activating cytotoxic T cells. Consequently, combining radiation therapy with immunotherapy represents an important area of research. Thus far, immune-checkpoint inhibitors targeting programmed death-ligand 1 (PD-L1), programmed cell death protein 1 (PD-1), and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) have been the focus of many research studies and clinical trials. The available data suggest that such immunotherapies are enhanced when combined with radiation therapy. However, treatment resistance, intrinsic or acquired, is still prevalent. Various theories as to how to enhance these combination therapies to overcome treatment resistance have been proposed. In this review, we focus on the principles surrounding radiation therapy's positive and negative effects on the tumor microenvironment. We explore mechanisms underlying radiation therapy's synergistic and antagonistic effects on immune responses and provide a base of knowledge for radio-immunology combination therapies to overcome treatment resistance. We provide evidence for targeting regulatory T cells, tumor-associated macrophages, and cancer-associated fibroblasts in combination radio-immunotherapies to improve cancer treatment.

Immunobiology of Radiotherapy: New Paradigms

Radiation Research, 2014

It has been well demonstrated that irradiated dying cancer cells release tumor antigens. The extracellular antigens and dying tumor cells are engulfed by circulating bone marrowderived antigen-presenting cells (APCs). After antigen uptake, APCs migrate to lymph nodes, where they engage with helper T cells for post-stimulation and APC activation. Induction of Th1 response and the activation of APCs further stimulate the induction of tumor specific cytotoxic T lymphocytes (CTLs) that could potentially clear tumor cells both at primary and metastatic sites (Fig. 1). Radiation-induced immune modulation happens in two important phases. First, radiation induces damage-associated molecular pattern (DAMP) molecules. In this event, radiation normalizes tumor vasculature, modulates tumor cell phenotype and increases immune recognition of the tumor cell. Radiation treatment can cause: a. upregulation of chemokines and adhesion molecules, providing signals for T cells to be attracted to the tumor; and b. upregulation of MHC molecules and tumor-associated antigens, making it easier for endogenous or immunotherapy-induced T cells to recognize and kill tumor (immunogenic modulation). Second, amplification by abrogating immune checkpoint factors with simultaneous costimulation of effector factors can ultimately lead to the induction of multiple unique T-cell populations (antigen cascade) that can kill antigen disparate tumor cells at metastatic sites (systemic effect) (Fig. 2). Radiation-Induced Immunomodulation This issue highlights novel findings and concepts on the immunobiology of radiation therapy coupled with translational concepts. Wattenberg et al. (1) reported on several cases where radiation modulates tumor cells to undergo immunogenic cell death or immunogenic modulation and this immune response is directly proportional to radiation dose. Current clinical radiotherapy regimens involve both hypo-and hyperfractionated treatments. Therefore, it is important to understand how immune genes respond to survival adaptation of irradiated tumor cells (during multifractionation as well as after single high-dose fraction) to

Immunologically augmented cancer treatment using modern radiotherapy

Radiation oncology has recently seen tremendous technical advances, resulting in increasing cancer cures. However, malignant neoplasias are systemic diseases and may be lethal even with an excellent tumor local control. Immune therapy has grown to a mature approach in oncology, delivering results impossible only a few years ago. Treatment-limiting mechanisms such as the immune suppressive tumor microenvironment are now to a large extent deciphered, allowing for pharmacological intervention. Interestingly, radiation-based treatment effects have been shown to depend to a large degree on the immune system. Applying the recent advances in radiation therapy in conjunction with immune therapy can be a turning point towards the long-standing aim of curing cancer. Only a detailed understanding of the molecular mechanisms can guide the implementation of combined therapy modalities.