The common HLA class I-restricted tumor-infiltrating T cell response in HPV16-induced cancer

Abstract

Immunotherapies targeting truly tumor-specific targets focus on the expansion and activation of T cells against neoantigens or oncogenic viruses. One target is the human papilloma virus type 16 (HPV16), responsible for several anogenital cancers and oropharyngeal carcinomas. Spontaneous and vaccine-induced HPV-specific T cells have been associated with better clinical outcome. However, the epitopes and restriction elements to which these T cells respond remained elusive. To identify CD8+ T cell epitopes in cultures of tumor infiltrating lymphocytes, we here used multimers and/or a functional screening platform exploiting single HLA class I allele-engineered antigen presenting cells. This resulted in the detection of 20 CD8+ T cell responses to 11 different endogenously processed HLA-peptide combinations within 12 HPV16-induced tumors. Specific HLA-peptide combinations dominated the response in patients expressing these HLA alleles. T cell receptors (TCRs) reactive to seven different HLA class I-restricted peptides could be isolated and analysis revealed tumor reactivity for five of the six TCRs analyzed. The tumor reactive TCRs to these dominant HLA class I peptide combinations can potentially be used to engineer tumor-specific T cells for adoptive cell transfer approaches to treat HPV16-induced cancers.

Dual T cell receptor/chimeric antigen receptor engineered NK‐92 cells targeting the HPV16 E6 oncoprotein and the tumor‐associated antigen L1CAM exhibit enhanced cytotoxicity and specificity against tumor cells

“…Previous studies using available prediction algorithms have identified a number of HLA class I‐restricted HPV16 E6 peptides. Of these, only a few are HLA‐A*02:01‐restricted and have been clinically validated, most notably the E6 29‐38 epitope 10,33 . Nevertheless, an E6‐reactive TCR specific to the E6 29‐38 epitope that was tested in a phase I clinical trial showed only two partial responses out of 12 treated patients 11 .…”

“…9 Later, a TCR reactive to the E6 29-38 peptide was identified from tumor infiltrating lymphocytes (TILs) of a cancer patient and tested in a phase I/II clinical trial, 10 albeit with limited success, with just two out of twelve patients showing partial responses. 11 No further clinical trials have been reported to date with the E6 [29][30][31][32][33][34][35][36][37][38] TCR. More recently, however, deep sequencing studies have identified several E6 variants in patients with high-grade squamous intraepithelial lesions (HSIL) caused by HPV16, with a hotspot located at codon 32.…”

The Tumor-Specific Immune Landscape in HPV+ Head and Neck Cancer

“…As mentioned above, relatively little work has been performed regarding HPV-specific TILs in HPV+ HNSCC. Prior works showed the presence of intratumoral HPV E6- and E7-specific CD4+ and CD8+ T cells, which predominantly secreted IFN-γ but also a substantial amount of IL-17, suggesting the intratumoral presence of HPV-specific T H 1 and T H 17 responses in HPV+ HNSCC ( Figure 1 ) [ 83 , 131 , 132 ]. However, additional information about the phenotypic and transcriptional landscape of HPV-specific TILs required to assess the differentiation state of these cells and their potential responsiveness to various treatment modalities has been lacking.…”

Identification of HPV16 E1 and E2-specific T cells in the oropharyngeal cancer tumor microenvironment

“…Open access that are critical components of antigen recognition and are influential in the outcome of viral infections. 14 15 Historically, numerous studies have focused on HPV16 E proteins E6 and E7 as targets of T-cell reactivity 16 and immunotherapy due to the established role of E6 and E7 in neoplastic transformation. [17][18][19][20][21][22][23] Despite limited early clinical successes targeting these antigens, durable complete tumor regression has been an elusive goal.…”

“…One epitope predicted to have high affinity in HPV16 E7-amino acids 11-19, was not predicted to be presented in HPV33 (online supplemental figure 2E). HPV16 E7 [11][12][13][14][15][16][17][18][19] has been reported to be a critical epitope in HPV16 recognition and has been the target of several Open trials seeking to treat HPV16-driven malignancies. 21 43 44 Therefore, we infer that a deficiency in HPV E7 recognition by T cells in HPV33 HLA-A*02:01+ may pose an elevated risk of virally-driven malignancy for this HPV genotype.…”