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HPV-independent head and neck squamous cell carcinoma (HNSCC) is a common cancer globally. The overall response rate to anti-PD1 checkpoint inhibitors (CPIs) in HNSCC is ~16%. One major factor influencing the effectiveness of CPI is the level of tumor infiltrating T cells (TILs). Converting TILlow tumors to TILhigh tumors is thus critical to improve clinical outcome. Here we describe a novel DNA vaccines to facilitate the T-cell infiltration and control tumor growth. We evaluated the expression of target antigens and their respective immunogenicity in HNSCC patients. The efficacy of DNA vaccines targeting two novel antigens were evaluated with or without CPI using a syngeneic model. Most HNSCC patients (43/44) co-expressed MAGED4B and FJX1 and their respective tetramer-specific T cells were in the range of 0.06-0.12%. In a preclinical model, antigen-specific T cells were induced by DNA vaccines and increased T cell infiltration into the tumor, but not MDSC or regulatory T cells. The vaccines inhibited tumor growth and improved the outcome alone and upon combination with anti-PD1 and resulted in tumor clearance in approximately 75% of mice. Pre-existence of MAGED4B and FJX1-reactive T cells in HNSCC patients suggests that these widely expressed antigens are highly immunogenic and could be further expanded by vaccination. The DNA vaccines targeting these antigens induced robust T cell responses and with the anti-PD1 antibody conferring excellent tumor control. This opens up an opportunity for combination immunotherapy that might benefit a wider population of HNSCC patients in an antigen-specific manner., Competing Interests: KL and NS received funding from Touchlight Genetics Ltd for translation of the preclinical work into early phase clinical testing. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Wang, Zainal, Chai, Dickie, Gan, Zulaziz, Lye, Sutavani, Ottensmeier, King, Abraham, Ismail, Lau, Kallarakkal, Mun, Zain, Abdul Rahman, Thomas, Cheong, Savelyeva and Lim.)

Head and neck cancer (HNC) is a heterogeneous group of squamous cell cancers that affect the oral cavity, pharynx, and larynx. Worldwide, it is the sixth most common cancer but in parts of Southern and South-East Asia, HNC is one of the most common cancers. A significant proportion of HNC is driven by human papillomavirus (HPV) infection, whereas HPV-independent HNC is associated with alcohol, smoking, and smokeless tobacco consumption. Here, we review the past and present experience of targeting HNC with vaccination focusing on HPV-derived antigens as well as non-viral antigens for HPV-negative HNC. Novel therapeutic approaches for HNC will focus not only on effective vaccine platforms but will also target the stroma-rich immunosuppressive microenvironment found in those tumours.

Increasing evidence has linked dysregulated interleukin (IL)-10 production by IL-10 +ve B cells to autoimmunity, highlighting the importance of improving the understanding of the regulation of IL-10 production in these cells. In both B cells and myeloid cells, IL-10 can be produced in response to Toll-like receptor (TLR) agonists. In macrophages, previous studies have established that mitogen- and stress-activated protein kinases (MSKs) regulate IL-10 production via the phosphorylation of cAMP response element-binding (CREB) protein on the IL-10 promoter. We found here that although MSKs are activated in peritoneal B cells in response to TLR4 agonists, neither MSKs nor CREB are required for IL-10 production in these cells. Using a combination of chemical inhibitors and knockout mice, we found that IL-10 induction in B cells was regulated by an ERK1/2- and p90 ribosomal S6 kinase-dependent mechanism, unlike in macrophages in which p90 ribosomal S6 kinase was not required. This observation highlights fundamental differences in the signaling controlling IL-10 production in B cells and macrophages, even though these two cell types respond to a common TLR stimulus., (© 2018 by The American Society for Biochemistry and Molecular Biology, Inc.)

The evolutionarily conserved protein kinase p38 mediates innate resistance to environmental stress and microbial infection. Four p38 isoforms exist in mammals and may have been co-opted for new roles in adaptive immunity. Murine T cells deficient in p38α, the ubiquitously expressed p38 isoform, showed no readily apparent cell-autonomous defects while expressing elevated amounts of another isoform, p38β. Mice with T cells simultaneously lacking p38α and p38β displayed lymphoid atrophy and elevated Foxp3 + regulatory T cell frequencies. Double deficiency of p38α and p38β in naïve CD4 + T cells resulted in an attenuation of MAPK-activated protein kinase (MK)-dependent mTOR signaling after T cell receptor engagement, and enhanced their differentiation into regulatory T cells under appropriate inducing conditions. Pharmacological inhibition of the p38-MK-mTOR signaling module produced similar effects, revealing potential for therapeutic applications., (© 2017 by The American Society for Biochemistry and Molecular Biology, Inc.)

Dendritic cell function is modulated by stromal cells, including fibroblasts. Although poorly understood, the signals delivered through this crosstalk substantially alter dendritic cell biology. This is well illustrated with release of TNF-α/IL-1β from activated dendritic cells, promoting PGE2 secretion from stromal fibroblasts. This instructs dendritic cells to up-regulate IL-23, a key Th17-polarizing cytokine. We previously showed that ionizing radiation inhibited IL-23 production by human dendritic cells in vitro. In the present study, we investigated the hypothesis that dendritic cell-fibroblast crosstalk overcomes the suppressive effect of ionizing radiation to support appropriately polarized Th17 responses. Radiation (1-6 Gy) markedly suppressed IL-23 secretion by activated dendritic cells (P < 0.0001) without adversely impacting their viability and consequently, inhibited the generation of Th17 responses. Cytokine suppression by ionizing radiation was selective, as there was no effect on IL-1β, -6, -10, and -27 or TNF-α and only a modest (11%) decrease in IL-12p70 secretion. Coculture with fibroblasts augmented IL-23 secretion by irradiated dendritic cells and increased Th17 responses. Importantly, in contrast to dendritic cells, irradiated fibroblasts maintained their capacity to respond to TNF-α/IL-1β and produce PGE2, thus providing the key intermediary signals for successful dendritic cell-fibroblasts crosstalk. In summary, stromal fibroblasts support Th17-polarizing cytokine production by dendritic cells that would otherwise be suppressed in an irradiated microenvironment. This has potential ramifications for understanding the immune response to local radiotherapy. These findings underscore the need to account for the impact of microenvironmental factors, including stromal cells, in understanding the control of immunity., (© The Author(s).)

Unlike other helper T cells, the costimulatory ligands responsible for T regulatory type 1 (Tr1) cell differentiation remain undefined. Understanding the molecular interactions driving peripheral Tr1 differentiation is important because Tr1s potently regulate immune responses by IL-10 production. In this study, we show that costimulation of human naive CD4(+) cells through CD97/CD55 interaction drives Tr1 activation, expansion, and function. T cell activation and expansion was equipotent with CD55 or CD28 costimulation; however, CD55 costimulation resulted in two IL-10-secreting populations. Most IL-10 was secreted by the minor Tr1 population (IL-10(high)IFN-γ(-)IL-4(-), <5% cells) that expresses Tr1 markers CD49b, LAG-3, and CD226. This Tr1 phenotype was not restimulated by CD28. However, on CD55 restimulation, Tr1s proliferated and maintained their differentiated IL-10(high) phenotype. The Tr1s significantly suppressed effector T cell function in an IL-10-dependent manner. The remaining (>95%) cells adopted a Th1-like IFN-γ(+) phenotype. However, in contrast to CD28-derived Th1s, CD55-derived Th1s demonstrated increased plasticity with the ability to coexpress IL-10 when restimulated through CD55 or CD28. These data identify CD55 as a novel costimulator of human Tr1s and support a role for alternative costimulatory pathways in determining the fate of the growing number of T helper populations. This study demonstrates that CD55 acts as a potent costimulator and activator of human naive CD4(+) cells, resulting in the differentiation of a discrete Tr1 population that inhibits T cell function in an IL-10-dependent manner and maintains the Tr1 phenotype upon restimulation.