The prototypic head and neck squamous cell carcinoma (HNSCC) arises from the mucosal lining of the upper aerodigestive tract, demonstrates squamous differentiation microscopically, involves older men ...with a long history of cigarette smoking and alcohol consumption, and is treated by multimodality therapy. HNSCC has long been regarded as a uniform disease process requiring a methodical and unwavering therapeutic approach. Divergence in epidemiologic trends among HNSCCs arising from different anatomic sites has introduced a view that, morphologic repetition aside, head and neck cancers form a heterogeneous group. This view has been supported at the molecular genetic level. A more complete understanding of the molecular genetics of head and neck cancer is providing new insights into long-held but poorly comprehended concepts such as field cancerization and is introducing various biomarkers with potential application for diagnosing, staging, monitoring, and prognosticating HNSCC.
Despite the availability of prophylactic human papillomavirus (HPV) vaccines, there is a growing incidence of HPV-associated head and neck squamous cell carcinomas (HPV-HNSCC) worldwide. The viral ...etiology of HPV-HNSCC provides an opportunity to develop personalized immune-based therapies, which target the unique viral- or tumor-specific proteins. Novel HPV-targeted immunotherapeutic approaches in clinical development are reviewed. Early results from these trials highlight new opportunities and potential challenges ahead. Immunotherapies for HPV-associated HNSCCs will require a tailored combinatorial approach based on preexisting mechanisms of host immune resistance. As the field continues to identify the relevant HPV types 16 and 18 immunogenic epitopes that are presented by diverse HLA class I alleles, improved HPV-targeted biologics and clinical monitoring tools can be developed and applied to a broader cancer patient population.
Human papillomavirus-associated head and neck squamous cell carcinomas (HPV-HNSCC) originate in the tonsils, the major lymphoid organ that orchestrates immunity to oral infections. Despite its ...location, the virus escapes immune elimination during malignant transformation and progression. Here, we provide evidence for the role of the PD-1:PD-L1 pathway in HPV-HNSCC immune resistance. We show membranous expression of PD-L1 in the tonsillar crypts, the site of initial HPV infection. In HPV-HNSCCs that are highly infiltrated with lymphocytes, PD-L1 expression on both tumor cells and CD68+ tumor-associated macrophages is geographically localized to sites of lymphocyte fronts, whereas the majority of CD8+ tumor-infiltrating lymphocytes express high levels of PD-1, the inhibitory PD-L1 receptor. Significant levels of mRNA for IFN-γ, a major cytokine inducer of PD-L1 expression, were found in HPV+ PD-L1(+) tumors. Our findings support the role of the PD-1:PD-L1 interaction in creating an "immune-privileged" site for initial viral infection and subsequent adaptive immune resistance once tumors are established and suggest a rationale for therapeutic blockade of this pathway in patients with HPV-HNSCC.
Anti-PD-1 immune checkpoint blockers can induce sustained clinical responses in cancer but how they function in vivo remains incompletely understood. Here, we combined intravital real-time imaging ...with single-cell RNA sequencing analysis and mouse models to uncover anti-PD-1 pharmacodynamics directly within tumors. We showed that effective antitumor responses required a subset of tumor-infiltrating dendritic cells (DCs), which produced interleukin 12 (IL-12). These DCs did not bind anti-PD-1 but produced IL-12 upon sensing interferon γ (IFN-γ) that was released from neighboring T cells. In turn, DC-derived IL-12 stimulated antitumor T cell immunity. These findings suggest that full-fledged activation of antitumor T cells by anti-PD-1 is not direct, but rather involves T cell:DC crosstalk and is licensed by IFN-γ and IL-12. Furthermore, we found that activating the non-canonical NF-κB transcription factor pathway amplified IL-12-producing DCs and sensitized tumors to anti-PD-1 treatment, suggesting a therapeutic strategy to improve responses to checkpoint blockade.
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•Effective anti-PD-1 anti-tumor responses require IL-12-producing dendritic cells•Anti-PD-1 indirectly activates IL-12 through IFN-γ produced from CD8+ T cells•Agonizing the non-canonical NF-κB pathway enhances dendritic cell IL-12 production•Combining aPD-1 with non-canonical NF-κB agonism enhances checkpoint immunotherapy
Anti-PD-1 mAbs can induce sustained clinical responses in cancer but how they function in vivo remains incompletely understood. Garris et al. show that effective anti-PD-1 immunotherapy requires intratumoral dendritic cells (DCs) producing IL-12. Anti-PD-1 indirectly activates DCs through IFN-γ released from drug-activated T cells. Furthermore, agonizing the non-canonical NF-κB pathway activates DCs and enhances aPD-1 therapy in an IL-12-dependent manner.
Checkpoint inhibitor therapy (CIT) has revolutionized cancer treatment but it has also reached a standstill when an absent dialog between cancer and immune cells makes it irrelevant. This occurs with ...high prevalence in the context of "immune silent" and, even perhaps, "immune-excluded" tumors. The latter are characterized by T cells restricted to the periphery of cancer nests. Since in either case T cells do not come in direct contact with most cancer cells, CIT rests immaterial. Adoptive cell therapy (ACT), may also be affected by limited access to antigen-bearing cancer cells. While lack of immunogenicity intuitively explains the immune silent phenotype, immune exclusion is perplexing. The presence of T cells at the periphery suggests that chemo-attraction recruits them and an immunogenic stimulus promotes their persistence. However, what stops the T cells from infiltrating the tumors' nests and reaching the germinal center (GC)? Possibly, a concentric gradient of increased chemo-repulsion or decreased chemo-attraction demarcates an abrupt "do not trespass" warning. Various hypotheses suggest physical or functional barriers but no definitive consensus exists over the weight that each plays in human cancers. On one hand, it could be hypothesized that the intrinsic biology of cancer cells may degenerate from a "cancer stem cell" (CSC)-like phenotype in the GC toward a progressively more immunogenic phenotype prone to immunogenic cell death (ICD) at the periphery. On the other hand, the intrinsic biology of the cancer cells may not change but it is the disorderly architecture of the tumor microenvironment (TME) that alters in a centripetal direction cancer cell metabolism, both directly and indirectly, the function of surrounding stromal cells. In this chapter, we examine whether the paradoxical exclusion of T cells from tumors may serve as a model to understand the requirements for tumor immune infiltration and, correspondingly, we put forth strategies to restore the dialog between immune cells and cancer to enhance the effectiveness of immune oncology (IO) approaches.
Tumor microenvironments (TMEs) influence cancer progression but are complex and often differ between patients. Considering that microenvironment variations may reveal rules governing intratumoral ...cellular programs and disease outcome, we focused on tumor-to-tumor variation to examine 52 head and neck squamous cell carcinomas. We found that macrophage polarity-defined by
and
(CS) expression but not by conventional M1 and M2 markers-had a noticeably strong prognostic association. CS macrophage polarity also identified a highly coordinated network of either pro- or antitumor variables, which involved each tumor-associated cell type and was spatially organized. We extended these findings to other cancer indications. Overall, these results suggest that, despite their complexity, TMEs coordinate coherent responses that control human cancers and for which CS macrophage polarity is a relevant yet simple variable.
Mutations 1 295 228 C>T and 1 295 250 C>T (termed C228T and C250T respectively), corresponding to -124 C>T and -146 C>T from the translation start site in the promoter of the telomerase reverse ...transcriptase (TERT) gene, have recently been reported in human cancers, but not in thyroid cancers yet. We explored these mutations in thyroid cancers by genomic sequencing of a large number of primary tumor samples. We found the C228T mutation in 0 of 85 (0.0%) benign thyroid tumors, 30 of 257 (11.7%) papillary thyroid cancers (PTC), 9 of 79 (11.4%) follicular thyroid cancers (FTC), 3 of 8 (37.5%) poorly differentiated thyroid cancers (PDTC), 23 of 54 (42.6%) anaplastic thyroid cancers (ATC), and 8 of 12 (66.7%) thyroid cancer cell lines. The C250T mutation was uncommon, but mutually exclusive with the C228T mutation, and the two mutations were collectively found in 11 of 79 (13.9%) FTC, 25 of 54 (46.3%) ATC, and 11 of 12 (91.7%) thyroid cancer cell lines. Among PTC variants, the C228T mutation was found in 4 of 13 (30.8%) tall-cell PTC (TCPTC), 23 of 187 (12.3%) conventional PTC, and 2 of 56 (3.6%) follicular variant PTC samples. No TERT mutation was found in 16 medullary thyroid cancer samples. The C228T mutation was associated with the BRAF V600E mutation in PTC, being present in 19 of 104 (18.3%) BRAF mutation-positive PTC vs 11 of 153 (7.2%) the BRAF mutation-negative PTC samples (P=0.0094). Conversely, BRAF mutation was found in 19 of 30 (63.3%) C228T mutation-positive PTC vs 85 of 227 (37.4%) C228T mutation-negative PTC samples (P=0.0094). We thus for the first time, to our knowledge, demonstrate TERT promoter mutations in thyroid cancers, that are particularly prevalent in the aggressive thyroid cancers TCPTC, PDTC, ATC and BRAF mutation-positive PTC, revealing a novel genetic background for thyroid cancers.
Several cancer immunotherapy approaches, such as immune checkpoint blockade and adoptive T-cell therapy, boost T-cell activity against the tumor, but these strategies are not effective in the absence ...of T cells specific for displayed tumor antigens. Here we outline an immunotherapy in which endogenous T cells specific for a noncancer antigen are retargeted to attack tumors. The approach relies on the use of antibody-peptide epitope conjugates (APECs) to deliver suitable antigens to the tumor surface for presention by HLA-I. To retarget cytomegalovirus (CMV)-specific CD8
T cells against tumors, we used APECs containing CMV-derived epitopes conjugated to tumor-targeting antibodies via metalloprotease-sensitive linkers. These APECs redirect pre-existing CMV immunity against tumor cells in vitro and in mouse cancer models. In vitro, APECs activated specifically CMV-reactive effector T cells whereas a bispecific T-cell engager activated both effector and regulatory T cells. Our approach may provide an effective alternative in cancers that are not amenable to checkpoint inhibitors or other immunotherapies.
High-risk human papillomavirus (HPV) is an established cause of head and neck carcinomas arising in the oropharynx. The presence of HPV has also been reported in some carcinomas arising in the ...sinonasal tract, but little is known about their overall incidence or their clinicopathologic profile. The surgical pathology archives of The Johns Hopkins Hospital were searched for all carcinomas arising in the sinonasal tract from 1995 to 2011, and tissue microarrays were constructed. p16 immunohistochemical analysis and DNA in situ hybridization for high-risk types of HPV were performed. Demographic and clinical outcome data were extracted from patient medical records. Of 161 sinonasal carcinomas, 34 (21%) were positive for high-risk HPV DNA, including type 16 (82%), type 31/33 (12%), and type 18 (6%). HPV-positive carcinomas consisted of 28 squamous cell carcinomas and variants (15 nonkeratinizing or partially keratinizing, 4 papillary, 5 adenosquamous, 4 basaloid), 1 small cell carcinoma, 1 sinonasal undifferentiated carcinoma, and 4 carcinomas that were difficult to classify but exhibited adenoid cystic carcinoma-like features. Immunohistochemistry for p16 was positive in 59/161 (37%) cases, and p16 expression strongly correlated with the presence of HPV DNA: 33 of 34 (97%) HPV-positive tumors exhibited high p16 expression, whereas only 26 of 127 (20%) HPV-negative tumors were p16 positive (P<0.0001). The HPV-related carcinomas occurred in 19 men and 15 women ranging in age from 33 to 87 years (mean, 54 y). A trend toward improved survival was observed in the HPV-positive group (hazard ratio=0.58, 95% confidence interval 0.26, 1.28). The presence of high-risk HPV in 21% of sinonasal carcinomas confirms HPV as an important oncologic agent of carcinomas arising in the sinonasal tract. Although nonkeratinizing squamous cell carcinoma is the most common histologic type, there is a wide morphologic spectrum of HPV-related disease that includes a variant that resembles adenoid cystic carcinoma. The distinctiveness of these HPV-related carcinomas of the sinonasal tract with respect to risk factors, clinical behavior, and response to therapy remains to be clarified.
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