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In the past decade, the field of cancer immunotherapy has been revolutionized by immune checkpoint blockade (ICB) technologies. Success across a broad spectrum of cancers has led to a paradigm shift in therapy for patients with advanced cancer. Early data are now accumulating in progressive thyroid cancers treated with single-agent ICB therapies and combination approaches that incorporate ICB technologies. This Review discusses our current knowledge of the immune response in thyroid cancers, the latest and ongoing immune-based approaches, and the future of immunotherapies in thyroid cancer. Physiologically relevant preclinical mouse models and human correlative research studies will inform development of the next stage of immune-based therapies for patients with advanced thyroid cancer.With immune checkpoint blockade (ICB) technologies increasingly being used in cancer immunotherapy, early data suggest that ICB therapies could be effective in thyroid cancer. This Review discusses our current knowledge of the immune response in thyroid cancers, the latest and ongoing immune-based approaches and the future of immunotherapies in thyroid cancer.

Abstract Context Although the development of immune checkpoint inhibitors has transformed treatment strategies of several human malignancies, research models to study immunotherapy in adrenocortical carcinoma (ACC) are lacking. Objective To explore the effect of anti-PD1 immunotherapy on the alteration of the immune milieu in ACC in a newly generated preclinical model and correlate with the response of the matched patient. Design, Setting, and Intervention To characterize the CU-ACC2-M2B patient-derived xenograft in a humanized mouse model, evaluate the effect of a PD-1 inhibitor therapy, and compare it with the CU-ACC2 patient with metastatic disease. Results Characterization of the CU-ACC2-humanized cord blood-BALB/c-Rag2nullIl2rγnullSirpaNOD model confirmed ACC origin and match with the original human tumor. Treatment of the mice with pembrolizumab demonstrated significant tumor growth inhibition (60%) compared with controls, which correlated with increased tumor infiltrating lymphocyte activity, with an increase of human CD8+ T cells (P < 0.05), HLA-DR+ T cells (P < 0.05) as well as Granzyme B+ CD8+ T cells (<0.001). In parallel, treatment of the CU-ACC2 patient, who had progressive disease, demonstrated a partial response with 79% to 100% reduction in the size of target lesions, and no new sites of metastasis. Pretreatment analysis of the patient's metastatic liver lesion demonstrated abundant intratumoral CD8+ T cells by immunohistochemistry. Conclusions Our study reports the first humanized ACC patient-derived xenograft mouse model, which may be useful to define mechanisms and biomarkers of response and resistance to immune-based therapies, to ultimately provide more personalized care for patients with ACC.

Cancer cells present neoantigens dominantly through MHC class I (MHCI) to drive tumor rejection through cytotoxic CD8+ T cells. There is growing recognition that a subset of tumors express MHC class II (MHCII), causing recognition of antigens by TCRs of CD4+ T cells that contribute to the antitumor response. We found that mouse BrafV600E-driven anaplastic thyroid cancers (ATCs) responded markedly to the RAF plus MEK inhibitors dabrafenib and trametinib (dab/tram) and that this was associated with upregulation of MhcII in cancer cells and increased CD4+ T cell infiltration. A subset of recurrent tumors lost MhcII expression due to silencing of Ciita, the master transcriptional regulator of MhcII, despite preserved IFN-γ signal transduction, which could be rescued by EZH2 inhibition. Orthotopically implanted Ciita-/- and H2-Ab1-/- ATC cells into immune-competent mice became unresponsive to the MAPK inhibitors. Moreover, depletion of CD4+, but not CD8+, T cells also abrogated the response to dab/tram. These findings implicate MHCII-driven CD4+ T cell activation as a key determinant of the response of Braf-mutant ATCs to MAPK inhibition.

This editorial reviews the recent paper by Ehlers et al and provides a perspective on thyroid cancer immunology.

Context: Although the development of immune checkpoint inhibitors has transformed treatment strategies of several human malignancies, research models to study immunotherapy in adrenocortical carcinoma (ACC) are lacking. Objective: To explore the effect of anti-PD1 immunotherapy on the alteration of the immune milieu in ACC in a newly generated preclinical model and correlate with the response of the matched patient. Design, Setting, and Intervention: To characterize the CU-ACC2-M2B patient-derived xenograft in a humanized mouse model, evaluate the effect of a PD-1 inhibitor therapy, and compare it with the CU-ACC2 patient with metastatic disease. Results: Characterization of the CU-ACC2-humanized cord blood-BALB/c-[Rag2.sup.null][Il2n/.sup.null][Sirpa.sup.WOD] model confirmed ACC origin and match with the original human tumor. Treatment of the mice with pembrolizumab demonstrated significant tumor growth inhibition (60%) compared with controls, which correlated with increased tumor infiltrating lymphocyte activity, with an increase of human CD8+ T cells (P < 0.05), HLA-DR+ T cells (P < 0.05) as well as Granzyme [B.sup.+] [CD8.sup.+] T cells (<0.001). In parallel, treatment of the CU-ACC2 patient, who had progressive disease, demonstrated a partial response with 79% to 100% reduction in the size of target lesions, and no new sites of metastasis. Pretreatment analysis of the patient's metastatic liver lesion demonstrated abundant intratumoral [CD8.sup.+] T cells by immunohistochemistry. Conclusions: Our study reports the first humanized ACC patient-derived xenograft mouse model, which may be useful to define mechanisms and biomarkers of response and resistance to immune-based therapies, to ultimately provide more personalized care for patients with ACC. (J Clin Endocrinol Metab 105: 26-42, 2020) Keywords: Adrenocortical carcinoma, anti-PD-1, humanized mouse PDX model, immunotherapy

γδ T cells are a diverse population of lymphocytes that play an important role in immune regulation. The size of the γδ T cell pool is tightly regulated, comprising only 1-10% of total lymphoid T cells in mice and humans. We examined the homeostatic regulation of γδ T cells using a model of lymphopenia-induced homeostatic expansion. We found that IL-15 and, to a lesser extent, IL-7 play an important role in lymphoid γδ T cell homeostasis. Moreover, γδ T cell homeostatic expansion was limited not only by γδ T cells themselves but also by natural killer cells and, αβ T cells. Our results suggest that CD8+αβ T cells are the most potent inhibitors of γδ T cell homeostasis and exert their effect by competing for IL-15.

There will be over half a million cancer-related deaths in the United States in 2012, with lung cancer being the leader followed by prostate in men and breast in women. There is estimated to be more than one and a half million new cases of cancer in 2012, making the development of effective therapies a high priority. As tumor immunologists, we are interested in the development of immunotherapies because the immune response offers exquisite specificity and the potential to target tumor cells without harming normal cells. In this review, we highlight the current advances in the field of immunotherapy and the current work being completed by laboratories at University of Colorado School of Medicine in multiple malignancies, including breast cancer, lung cancer, melanoma, thyroid cancer, and glioblastoma. This work focuses on augmenting the anti-tumor response of CD8 T cells in the blood, lymph nodes, and tumors of patients, determining biomarkers for patients who are more likely to respond to immunotherapy, and identifying additional anti-tumor and immunosuppressive cells that influence the overall response to tumors. These collaborative efforts will identify mechanisms to improve immune function, which may elucidate therapeutic targets for clinical trials to improve patient health and survival.

Lymphocytes expressing gamma delta T cell receptors (TCR) constitute an entire system of functionally specialized subsets that have been implicated in the regulation of immune responses, including responses to pathogens and allergens, and in tissue repair. The gamma delta TCRs share structural features with adaptive receptors and peripheral selection of gamma delta T cells occurs. Nevertheless, their specificities may be primarily directed at self-determinants, and the responses of gamma delta T cells exhibit innate characteristics. Continuous cross talk between gamma delta T cells and myeloid cells is evident in histological studies and in in vitro co-culture experiments, suggesting that gamma delta T cells play a functional role as an integral component of the innate immune system.

Cancer cells present neoantigens dominantly through MHC class I (MHCI) to drive tumor rejection through cytotoxic CD8+ T-cells. There is growing recognition that a subset of tumors express MHC class II (MHCII), causing recognition of antigens by TCRs of CD4+ T-cells that contribute to the anti-tumor response. We find that mouse Braf -driven anaplastic thyroid cancers (ATC) respond markedly to the RAF + MEK inhibitors dabrafenib and trametinib (dab/tram) and that this is associated with upregulation of MhcII in cancer cells and increased CD4+ T-cell infiltration. A subset of recurrent tumors lose MhcII expression due to silencing of , the master transcriptional regulator of MhcII, despite preserved interferon gamma signal transduction, which can be rescued by EZH2 inhibition. Orthotopically-implanted Ciita and H2-Ab1 ATC cells into immune competent mice become unresponsive to the MAPK inhibitors. Moreover, depletion of CD4+, but not CD8+ T-cells, also abrogates response to dab/tram. These findings implicate MHCII-driven CD4+ T cell activation as a key determinant of the response of Braf-mutant ATCs to MAPK inhibition.