Head and neck squamous cell carcinomas (HNSCCs) are highly aggressive, multi-factorial tumors in the upper aerodigestive tract affecting more than half a million patients worldwide each year. Alcohol, tobacco, and human papillomavirus (HPV) infection are well known causative factors for HNSCCs. Current treatment options for HNSCCs are surgery, radiotherapy, chemotherapy, or combinatorial remedies. Over the past decade, despite the marked improvement in clinical outcome of many tumor types, the overall 5-year survival rate of HNSCCs remained ∼40–50% largely due to poor availability of effective therapeutic options for HNSCC patients with recurrent disease. Therefore, there is an urgent and unmet need for the identification of specific molecular signatures that better predict the clinical outcomes and markers that serve as better therapeutic targets. With recent technological advances in genomic and epigenetic analyses, our knowledge of HNSCC molecular characteristics and classification has been greatly enriched. Clinical and genomic meta-analysis of multicohort HNSCC gene expression profile has clearly demonstrated that HPV + and HPV - HNSCCs are not only derived from tissues of different anatomical regions, but also present with different mutation profiles, molecular characteristics, immune landscapes, and clinical prognosis. Here, we briefly review our current understanding of the biology, molecular profile, and immunological landscape of the HPV + and HPV - HNSCCs with an emphasis on the diversity and heterogeneity of HNSCC clinicopathology and therapeutic responses. After a review of recent advances and specific challenges for effective immunotherapy of HNSCCs, we then conclude with a discussion on the need to further enhance our understanding of the unique characteristics of HNSCC heterogeneity and the plasticity of immune landscape. Increased knowledge regarding the immunological characteristics of HPV + and HPV - HNSCCs would improve therapeutic targeting and immunotherapy strategies for different subtypes of HNSCCs.

Summary Adaptation of malignant cells to the hostile milieu present in tumors is an important determinant for their survival and growth. However, the interaction between tumor-linked stress and anti-tumor immunity remains poorly characterized. Here, we show the critical role of the cellular stress sensor C/EBP-homologous protein (Chop) in the accumulation and immune inhibitory activity of tumor-infiltrating myeloid-derived suppressor cells (MDSCs). MDSCs lacking Chop had decreased immune regulatory functions and showed the ability to prime T cell function and induce anti-tumor responses. Chop expression in MDSCs was induced by tumor-linked reactive oxygen and nitrogen species and regulated by the activating-transcription factor-4. Chop-deficient MDSCs displayed reduced signaling through CCAAT/enhancer-binding protein-β, leading to a decreased production of interleukin-6 (IL-6) and low expression phospho-STAT3. IL-6 over-expression restored immune suppressive activity of Chop-deficient MDSCs. These findings suggest the role of Chop in tumor-induced tolerance and the therapeutic potential of targeting Chop in MDSCs for cancer immunotherapy.

Lentiviruses infect both dividing and nondividing cells. In in pHP. The ability of this vector system to transduce dividthis study we characterized a lentiviral vector system coning and nondividing cell in vitro and in vivo was also demsisting of a packaging vector (pHP) and a transducing veconstrated. Compared with a Moloney murine leukemia tor (pTV) derived from a recombinant human immunodefivirus (MLV) vector, the HP/TV vectors transduced human ciency virus type 1 (HIV-1). In pHP, the long terminal muscle-, kidney-, liver-derived cell lines and CD34 + primary repeats (LTRs), the 5Ј untranslated leader and portions of hematopoietic progenitor cells more efficiently. Although the env and nef genes were deleted. The leader sequence the levels of the pTV transgene expression were high soon of pHP was substituted with a modified Rous sarcoma virus after transduction, the expression tended to decrease with (RSV) 59 bp leader containing a mutated RSV gag AUG time due either to the loss of proviral DNA or to the inactiand a functional 5Ј splice site. The pHP construct was vation of promoter activity, which was found to be cell typefound to direct Gag-Pol synthesis as efficiently as wild-type dependent. Analyses of extrachromosomal DNA showed HIV-1. The pTV construct contains sequences required for that the unintegrated proviral DNA of lentiviral vectors sur-RNA packaging, reverse transcription and integration, but vived much longer than that of the retroviral vectors. We lacks viral genes. Co-transfection of pHP, pTV and a vesdemonstrate that the HP/TV vector is capable of high icular stomatitis virus G (VSV-G) envelope plasmid proefficiency transduction and that long-term expression of duced vectors at titers of 10 5 -10 6 transducing units per lentiviral vectors is dependent on target cell type, the milliliter in 48 h. Replication-competent virus (RCV) was internal promoter and the transgene itself in the transducnot detected when deletions were made in the env gene ing vector.

We show that in vitro activation of interphotoreceptor retinoid-binding protein (IRBP)-specific T cells from C57BL/6 mice immunized with an uveitogenic IRBP peptide (IRBP1–20) under TH17-polarizing conditions is associated with increased expansion of T cells expressing the γδ TCR. We also show that highly purified αβ or γδ T cells from C57BL/6 mice immunized with IRBP1–20 produced only small amounts of IL-17 after exposure to the immunizing Ag in vitro, whereas a mixture of the same T cells produced greatly increased amounts of IL-17. IRBP-induced T cells from IRBP-immunized TCR-γ−/−mice on the C57BL/6 genetic background produced significantly lower amounts of IL-17 than did wild-type C57BL/6 mice and had significantly decreased experimental autoimmune uveitis-inducing ability. However, reconstitution of the TCR-γ−/−mice before immunization with a small number of γδ T cells from IRBP-immunized C57BL/6 mice restored the disease-inducing capability of their IRBP-specific T cells and greatly enhanced the generation of IL-17+ T cells in the recipient mice. Our study suggests that γδ T cells are important in the generation and activation of IL-17-producing autoreactive T cells and play a major role in the pathogenesis of experimental autoimmune uveitis.