The role of mitochondria in cancer formation and progression has been studied extensively, but much remains to be understood about this complex relationship. Mitochondria regulate many processes that are known to be altered in cancer cells, from metabolism to oxidative stress to apoptosis. Here, we review the evolving understanding of the role of mitochondria in cancer cells, and highlight key evidence supporting the role of mitochondria in cancer immune evasion and the effects of mitochondria-targeted antitumor therapy. Also considered is how knowledge of the role of mitochondria in cancer can be used to design and improve cancer therapies, particularly immunotherapy and radiation therapy. We further offer critical insights into the mechanisms by which mitochondria influence tumor immune responses, not only in cancer cells but also in immune cells. Given the central role of mitochondria in the complex interactions between cancer and the immune system, high priority should be placed on developing rational strategies to address mitochondria as potential targets in future preclinical and clinical studies. We believe that targeting mitochondria may provide additional opportunities in the development of novel antitumor therapeutics.

We have previously demonstrated that PD-1 blockade decreased the incidence of high-grade dysplasia in a carcinogen-induced murine model of oral squamous cell carcinoma (OSCC). It remains unknown, however, whether there are additional factors involved in escape from immune surveillance that could serve as additional targets for immunoprevention. We performed this study to further characterize the immune landscape of oral premalignant lesions (OPL) and determine the impact of targeting of the PD-1, CTLA-4, CD40, or OX40 pathways on the development of OPLs and oral carcinomas in the 4-nitroquinoline 1-oxide model. The immune pathways were targeted using mAbs or, in the case of the PD-1/PD-L1 pathway, using PD-L1–knockout (PD-L1ko) mice. After intervention, tongues and cervical lymph nodes were harvested and analyzed for malignant progression and modulation of the immune milieu, respectively. Targeting of CD40 with an agonist mAb was the most effective treatment to reduce transition of OPLs to OSCC; PD-1 alone or in combination with CTLA-4 inhibition, or PD-L1ko, also reduced progression of OPLs to OSCC, albeit to a lesser extent. Distinct patterns of immune system modulation were observed for the CD40 agonists compared with blockade of the PD-1/PD-L1 axis with or without CTLA-4 blockade; CD40 agonist generated a lasting expansion of experienced/memory cytotoxic T lymphocytes and M1 macrophages, whereas PD-1/CTLA-4 blockade resulted in a pronounced depletion of regulatory T cells among other changes. These data suggest that distinct approaches may be used for targeting different steps in the development of OSCC, and that CD40 agonists merit investigation as potential immunoprevention agents in this setting. Prevention Relevance: PD-1/PD-L1 pathway blockade, as well as activation of the CD40 pathway, were able to prevent OPL progression into invasive OSCC in a murine model. A distinct pattern of immune modulation was observed when either the CD40 or the PD-1/PD-L1 pathways were targeted.

Oral squamous cell carcinomas represent a significant cancer burden worldwide. Unfortunately, chemoprevention strategies investigated to date have failed to produce an agent considered standard of care to prevent oral cancers. Nonetheless, recent advances in clinical trial design may streamline drug development in this setting. In this manuscript, we review some of these improvements, including risk prediction tools based on molecular markers that help select patients most suitable for chemoprevention. We also discuss the opportunities that novel preclinical models and modern molecular profiling techniques will bring to the prevention field in the near future, and propose a clinical trials framework that incorporates molecular prognostic factors, predictive markers and cancer biology as a roadmap to improve chemoprevention strategies for oral cancers. A major global health concern, oral squamous cell carcinoma (OSCC) is currently the 13th most common cancer worldwide, with an estimate of 300,000 new cases, and 145,000 deaths each year [1]. Tobacco, alcohol and/or betel nut exposure are well-established risk factors for OSCC. Interruption of carcinogen use is an obvious key intervention to reduce oral cancer incidence ('primary' prevention). Nonetheless, OSCC risk remains elevated even after alcohol and tobacco cessation and may take up to 20 years to reach baseline levels [2] illustrating the need for development of approaches that can interrupt/reverse the process of carcinogenesis after initiation, but before full malignant transformation. Furthermore, an increase in the incidence of oral cancer in women with no clear etiologic factors has been observed [3], supporting the need for improved understanding of molecular pathways dysregulation that lead to cancer and how they could be targeted for OSSC prevention.Oral potentially malignant lesions (OPMLs) are often clinically characterized as leukoplakia and/or erythroplakia. Histologically, these lesions frequently exhibit hyperplasia, hyperkeratosis and/or varying degrees of dysplasia (i.e., intraepithelial neoplasias [IEN]). OPMLs are not obligate precursors of oral cancers, but they are estimated to precede development of at least 7% of OSCC [4] OPMLs are in and of themselves risk factors for oral cancer, but have a variable frequency of malignant transformation, depending on other clinical, demographic, etiologic, histological and/or molecular features [5]. The anatomic accessibility of OPMLs for examination and biopsies provides an opportunity for clinical and translational studies of oral carcinogenesis. In this review, we will summarize the recent advances and future perspectives of molecularly focused strategies of oral cavity cancers chemoprevention, many of which stem from OPML-based research. We will specifically

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