Radiotherapy is intriguing as it not only eliminates tumor cells but also triggers a response from cytotoxic T cells, which attack the tumor. Thus, radiotherapy and immunotherapy are being combined... Show moreRadiotherapy is intriguing as it not only eliminates tumor cells but also triggers a response from cytotoxic T cells, which attack the tumor. Thus, radiotherapy and immunotherapy are being combined in clinical studies, although their success has been limited. We used mouse tumor models to understand how radiotherapy induces T cell priming and subsequent anti-tumor immunity. In a model resembling lymphocyte-depleted cancer, we identified obstacles to systemic radiotherapy-induced T cell responses and proposed interventions to overcome them. Additionally, we explored strategies to counter local T cell suppression in the tumor microenvironment. In poorly immunogenic tumors, radiotherapy can provoke a T cell response, but this is counteracted by the generation of immunosuppressive Tregs. Combining radiotherapy with checkpoint immunotherapy, despite its success in humans, unexpectedly amplified the Treg response, further hindering cytotoxic T-cell activity. Our findings suggest this immunotherapy may not benefit these cancers. We discovered that molecules like CD80 and CD86, capable of stimulating T cells via the CD28 receptor, have distinct roles in promoting cytotoxic and Treg cells. Blocking CD86 enhanced cytotoxic T cell responses post-radiotherapy, leading to tumor rejection. Our study elucidates how tumor characteristics shape T-cell responses, how radiotherapy can evoke both favorable and unfavorable responses, and how targeted antibody immunotherapy can influence this interplay. Show less
This thesis focuses on treatment outcomes of high risk endometrial cancer and corresponding patients’ and clinicians’ preferences regarding adjuvant treatment decisions; molecular studies on the... Show moreThis thesis focuses on treatment outcomes of high risk endometrial cancer and corresponding patients’ and clinicians’ preferences regarding adjuvant treatment decisions; molecular studies on the etiology of mismatch repair deficiency (MMRd) in intermediate and high risk endometrial cancer; and the combination of immunotherapy and PARP inhibition for the treatment of recurrent or metastatic endometrial cancer.The overall aims of this thesis were:• To evaluate health-related quality of life up to 5 years after chemoradiotherapy compared with pelvic radiotherapy alone in the adjuvant treatment of high risk endometrial cancer in the PORTEC-3 trial;• To investigate the preferences of patients and clinicians regarding the benefit-risk trade-off of the addition of chemotherapy to adjuvant pelvic radiotherapy;• To investigate the prevalence and prognosis of Lynch syndrome-associated endometrial cancer among MMRd endometrial cancers;• To evaluate the role of combined checkpoint inhibition and PARP inhibition in women with metastatic or recurrent endometrial cancer in terms of progression-free survival and toxicity in the DOMEC trial. Show less
This thesis sought to obtain a better understanding of the composition of the immune microenvironment in NSCLC and how to modulate this tumor immune microenvironment by RT to induce amplified... Show moreThis thesis sought to obtain a better understanding of the composition of the immune microenvironment in NSCLC and how to modulate this tumor immune microenvironment by RT to induce amplified antitumor immune responses to ICIs in advanced NSCLC patients. In the first part of this thesis, a multiangular approach of a combination of protein and mRNA expression with clinicopathological characteristics in a large cohort of early stage, resected NSCLC samples will be discussed. The second part focusses on the immune modulating effects of RT, in particular when combined with immunotherapy treatment in metastatic NSCLC. Show less
Immunotherapy has obtained a secure place in the treatment of metastatic non-small cell lung cancer (NSCLC) and has made a great impact on prognosis of responders. Unfortunately, not all NSCLC... Show moreImmunotherapy has obtained a secure place in the treatment of metastatic non-small cell lung cancer (NSCLC) and has made a great impact on prognosis of responders. Unfortunately, not all NSCLC patients derive benefit from this treatment. Several immune escape mechanisms have been postulated, explaining failure of tumor immune attack. A better understanding of these mechanisms helps us to seek treatment strategies to overcome resistance to immunotherapy. Radiotherapy has immunomodulatory qualities capable of enhancing the anticancer immune response by tackling a number of these tumor escape mechanisms. In this review, we focus on mechanisms of off-target effects of radiotherapy, the so-called abscopal effect, by describing the current role of immune checkpoint inhibitors (ICIs) in NSCLC, the possible reasons for its failures and evidence on how radiotherapy may be able to counteract these mechanisms. An oversight of pre-clinical and clinical data supporting augmentation of abscopal events by radiotherapy when combined with ICIs is presented. As much remains unclear regarding optimal dose, fractionation, target volume or timing of radiation therapy, future research will need to focus on implementing data from pre-clinical and translational findings in the development of new clinical trials in order to help optimizing the potential of the combination of immunotherapy with radiotherapy. Show less
