BRAF^V600E and BRAF-WT Specific Antitumor Immunity in Papillary Thyroid Cancer

Abstract

One feature of papillary thyroid cancer (PTC) is the frequently present somatic BRAF^V600E mutation. PTCs are also characterized by a lymphocytic infiltration, which may correlate with an improved clinical outcome. The objective of the study was the characterization of BRAF^V600E specific anti-immunity in PTC patients and correlation analyses with the clinical outcome. Fourteen HLA A2 positive PTC patients were included into the study of whom tumor tissue samples were also available. Of those, 8 PTC patients revealed a somatic BRAF^V600E mutation. All PTC patients were also MHC class II typed. Tetramer analyses for detection of MHC class I and MHC class II-restricted, BRAF^V600E epitope-specific T cells using unstimulated and peptide-stimulated T cells were performed; correlation analyses between MHC phenotypes, T cell immunity, and the clinical course were performed. In regard to unstimulated T cells, a significantly higher amount of BRAF^V600E epitope specific T cells was detected compared to a control tetramer. Importantly, after overnight peptide stimulation a significantly higher number of BRAF^V600E positive and BRAF WT epitope-specific T cells could be seen. In regard to the clinical course, however, no significant differences were seen, neither in the context of the initial tumor size, nor in the context of lymph node metastases or peripheral metastastic spread. In conclusion, we clearly demonstrated a BRAF-specific tumor immunity in PTC-patients which is, however, independent of a BRAF^V600E status of the PTC patients.

Key words

papillary thyroid carcinoma - BRAF - antitumor immunity - tetramer analysis

Publication History

Received: 25 July 2022

Accepted after revision: 20 October 2022

Article published online:
25 November 2022

• References

• 1 La Vecchia C, Malvezzi M, Bosetti C. et al. Thyroid cancer mortality and incidence: a global overview. Int J Cancer 2015; 136: 2187-2195
• 2 Ajjan RA, Weetman AP. The pathogenesis of Hashimoto’s thyroiditis: further developments in our understanding. Horm Metab Res 2015; 47: 702-710
• 3 Pellegriti G, Frasca F, Regalbuto C. et al. Worldwide increasing incidence of thyroid cancer: update on epidemiology and risk factors. J Cancer Epidemiol 2013; 10
• 4 Eichhorn W, Tabler H, Lippold R. et al. Prognostic factors determining long-term survival in well-differentiated thyroid cancer: an analysis of four hundred eighty-four patients undergoing therapy and aftercare at the same institution. Thyroid 2003; 13: 949-958
• 5 Matsubayashi S, Kawai K, Matsumoto Y. et al. The correlation between papillary thyroid carcinoma and lymphocytic infiltration in the thyroid gland. J Clin Endocrinol Metab 1995; 80: 3421-3424
• 6 Ehlers M, Thiel A, Bernecker C. et al. Evidence of a combined cytotoxic thyroglobulin and thyroperoxidase epitope-specific cellular immunity in Hashimoto’s thyroiditis. J Clin Endocrinol Metab 2012; 97: 1347-1354
• 7 Xing M, Alzahrani AS, Carson KA. et al. Association between BRAF V600E mutation and mortality in patients with papillary thyroid cancer. JAMA 2013; 309: 1493-1501
• 8 Xing M, Alzahrani AS, Carson KA. et al. Association between BRAF V600E mutation and recurrence of papillary thyroid cancer. J Clin Oncol 2015; 33: 42-50
• 9 Cancer Genome Atlas Research N Integrated genomic characterization of papillary thyroid carcinoma. Cell 2014; 159: 676-690
• 10 Kim KH, Kang DW, Kim SH. et al. Mutations of the BRAF gene in papillary thyroid carcinoma in a Korean population. Yonsei Med J 2004; 45: 818-821
• 11 Namba H, Nakashima M, Hayashi T. et al. Clinical implication of hot spot BRAF mutation, V599E, in papillary thyroid cancers. J Clin Endocrinol Metab 2003; 88: 4393-4397
• 12 Champion KJ, Bunag C, Estep AL. et al. Germline mutation in BRAF codon 600 is compatible with human development: de novo p.V600G mutation identified in a patient with CFC syndrome. Clin Genet 2011; 79: 468-474
• 13 Chapman PB, Hauschild A, Robert C. et al. Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N Engl J Med 2011; 364: 2507-2516
• 14 Chapman PB, Robert C, Larkin J. et al. Vemurafenib in patients with BRAFV600 mutation-positive metastatic melanoma: final overall survival results of the randomized BRIM-3 study. Ann Oncol 2017; 28: 2581-2587
• 15 McArthur GA, Maio M, Arance A. et al. Vemurafenib in metastatic melanoma patients with brain metastases: an open-label, single-arm, phase 2, multicentre study. Ann Oncol 2017; 28: 634-641
• 16 Shabaneh TB, Molodtsov AK, Steinberg SM. et al. Oncogenic BRAF(V600E) governs regulatory T-cell recruitment during melanoma tumorigenesis. Cancer Res 2018; 78: 5038-5049
• 17 Shi H, Hugo W, Kong X. et al. Acquired resistance and clonal evolution in melanoma during BRAF inhibitor therapy. Cancer Discov 2014; 4: 80-93
• 18 Veatch JR, Lee SM, Fitzgibbon M. et al. Tumor infiltrating BRAFV600E-specific CD4 T cells correlated with complete clinical response in melanoma. J Clin Invest 2018; 128: 1563-1568
• 19 Ehlers M, Kuebart A, Hautzel H. et al. Epitope-specific antitumor immunity suppresses tumor spread in papillary thyroid cancer. J Clin Endocrinol Metab 2016; jc20162469
• 20 Somasundaram R, Swoboda R, Caputo L. et al. Human leukocyte antigen-A2-restricted CTL responses to mutated BRAF peptides in melanoma patients. Cancer Res 2006; 66: 3287-3293
• 21 Rammensee H, Bachmann J, Emmerich NP, Bachor OA, Stevanovic S. SYFPEITHI: database for MHC ligands and peptide motifs. Immunogenetics 1999; 50: 213-219
• 22 Immunogenetics ASFH. 2022