Oral squamous cell carcinoma (OSCC) remains an understudied and significant global cancer killer and dismal survival rates have not changed in decades. A better understanding of the molecular basis of OSCC progression and metastasis is needed to develop new approaches for treating this disease. The supportive network surrounding cancer tumor cells known as the tumor microenvironment (TME) has gained increasing interest lately since it performs essential protumorigenic functions. Cancer-associated fibroblasts (CAFs) are one of the main cell types in the TME and are known to play a key role in influencing the biological behavior of tumors. CAFs present a heterogeneity both in phenotype as well as functions, leading to the suggestion of different CAF subtypes in several cancer forms. The task to subtype CAFs in OSCC has, however, just begun, and there is today no united way of subtyping CAFs in this disease. This review aims to define the features of CAFs and to summarize CAF subtype research in malignancy with focus on OSCC including aspects as disease prognosis and therapeutic opportunities.

Immunotherapy has changed the way many cancers are being treated. Researchers in the field of immunotherapy and tumor immunology are investigating similar questions: How can the positive benefits achieved with immunotherapies be enhanced? Can this be achieved through combinations with other agents and if so, which ones? In our view, there is an urgent need to improve immunotherapy to make further gains in the overall survival for those patients that should benefit from immunotherapy. While numerous different approaches are being considered, our team believes that drug delivery methods along with appropriately selected small-molecule drugs and drug candidates could help reach the goal of doubling the overall survival rate that is seen in some patients that are given immunotherapeutics. This review article is prepared to address how immunotherapies should be combined with a second treatment using an approach that could realize therapeutic gains 10 years from now. For context, an overview of immunotherapy and cancer angiogenesis is provided. The major targets in angiogenesis that have modulatory effects on the tumor microenvironment and immune cells are highlighted. A combination approach that, for us, has the greatest potential for success involves treatments that will normalize the tumor’s blood vessel structure and alter the immune microenvironment to support the action of immunotherapeutics. So, this is reviewed as well. Our focus is to provide an insight into some strategies that will engender vascular normalization that may be better than previously described approaches. The potential for drug delivery systems to promote tumor blood vessel normalization is considered.

Background: Radiation therapy is commonly used to treat head and neck cancer patients, and response may be improved by combining radiation with preexisting medications. Based on recent preclinical and retrospective patient data, we hypothesized that antihypertensive drugs may improve radiotherapy outcomes. Methods: Retrospective analyses were conducted on 1077 oropharyngeal squamous cell carcinoma and 608 nasopharyngeal carcinoma patients, all of whom received radiation therapy. Univariate and multivariate analyses were conducted to assess overall survival, disease-specific survival, and locoregional control for cancer patients taking angiotensin receptor blockers (ARBs), angiotensin-converting enzyme inhibitors, calcium channel blockers, or beta blockers compared with propensity score–matched groups of patients not taking these medications. Results: Oropharyngeal squamous cell carcinoma patients taking antihypertensive medications were statistically older and had higher Charlson Comorbidity Indices at diagnosis. However, these patients had statistically significant improved overall survival, disease-specific survival, and locoregional control compared with propensity score–matched oropharyngeal squamous cell carcinoma patients who were not taking antihypertensive medications, with ARB users showing the greatest improvements. Antihypertensive drugs did not affect outcomes in the nasopharyngeal carcinoma patient cohort. Conclusion: The use of antihypertensive medications, and particularly ARBs, was associated with improved outcomes in oropharyngeal squamous cell carcinoma patients who had more advanced age and higher Charlson Comorbidity Indices at diagnosis. This study supports future prospective testing of ARBs in conjunction with radiation therapy in this group of higher risk oropharyngeal squamous cell carcinoma patients. Additionally, this study illustrates the need to use propensity score matching to identify patient subgroups that may benefit from a given treatment in retrospective analyses.

Poorly oxygenated (hypoxic) cells are key components of the solid tumor microenvironment and are well-established contributors to poor therapeutic outcome. Patients with tumors that contain hypoxic cells have worse outcome after radiotherapy, chemotherapy, and surgery, underscoring the therapeutic relevance of hypoxia in driving more aggressive tumor phenotypes. Angiotensin II type 1 receptor (AT1R) blockers (ARBs) are widely prescribed anti-hypertensive agents that inhibit the activity of angiotensin II derived from the renin-angiotensin system. ARBs have also been shown to exhibit anti-fibrotic activity by inhibiting AT1R expressed on myofibroblasts. We recently reported that the ARB telmisartan inhibits collagen I (Col1) deposition in solid tumors, increasing net tumor perfusion, stabilizing microregional tumor blood flow, and decreasing tumor hypoxia. Cancer-associated fibroblasts (CAFs) produce Col1, although recent clinical data indicate the presence of multiple, functionally-diverse CAF subsets in tumors from patients with breast or ovarian cancer. To further explore how ARBs and CAFs affect the solid tumor microenvironment, we were interested in whether murine CAF subsets are present in human tumor xenografts and, if so, whether telmisartan preferentially influences collagen-producing CAF subsets in solid tumors. We were also interested in whether telmisartan affects collagen deposition, hypoxia, and radiation response in head & neck and cervix tumors that are commonly treated with ionizing radiation therapy. We then asked whether head & neck cancer patients taking ARBs as anti-hypertensive medications have quantifiably different tumor microenvironments and improved therapeutic outcome. Using a panel of six human head & neck and cervix tumor xenografts, we identified four unique subsets (S1-S4) of CAFs that are present at varying levels in the different tumor lines. Telmisartan significantly altered the CAF content of tumors while also reducing CAF-mediated collagen deposition in the tumor microenvironment. We found that telmisartan also decreased tumor hypoxia and improved radiation response in our pre-clinical models, indicating that CAF subsets help to create hypoxia and contribute to radioresistance of solid tumors in an AT1R-dependent manner. Using a retrospective cohort of over 1,100 oropharyngeal cancer patients, we found that patients taking ARBs had dramatically improved therapeutic outcomes after radiation therapy, validating our pre-clinical data and supporting the further development and testing of ARBs as neoadjuvant therapies for patients with hypoxic tumors. Understanding how the solid tumor microenvironment influences cancer therapy is central to improving treatment outcome, and our work identifies CAFs as key contributors to the development of hypoxia in solid tumors. Repurposing clinically approved, anti-hypertensive ARBs represents a novel therapeutic strategy to inhibit CAF activity, modify the solid tumor microenvironment, reduce tumor hypoxia, and improve radiation response. Citation Format: Brennan J. Wadsworth, Che-Min Lee, Ryan Urban, Sarah N. Hamilton, Kevin L. Bennewith. Angiotensin II receptor blockers modify the solid tumor microenvironment and improve radiation therapy response [abstract]. In: Proceedings of the AACR Virtual Special Conference on Radiation Science and Medicine; 2021 Mar 2-3. Philadelphia (PA): AACR; Clin Cancer Res 2021;27(8_Suppl):Abstract nr PR-001.

Cancer associated fibroblasts (CAFs) are the main contributors to fibrosis in solid tumours. Fibrosis can lead to increased tumoural stiffness, immune cell exclusion, and poor response to cancer therapies. However, therapeutically depleting CAFs has been shown to increase tumour progression and metastasis in some pre-clinical tumour models. Targeted approaches to inhibit CAF activity and decrease fibrosis without abrogating CAFs altogether may improve the effect of existing cancer therapies. We have previously shown that the blood pressure medication telmisartan decreases tumoural collagen, resulting in improved vascular perfusion, decreased hypoxia, and improved radiation treatment efficacy. To understand how telmisartan influences CAF populations in solid tumours, we conducted single cell RNA sequencing analyses of host cells isolated from tumours in mice treated with telmisartan. Telmisartan modified the transcriptomes of CAF populations, promoting the expression of chemokine signaling while decreasing the expression of extracellular matrix components in myCAFs. Telmisartan decreased expression of collagen transcripts in myCAFs and fibrocytes, indicating that telmisartan does not remove myCAFs but changes the myCAF transcriptome to become less fibrillar. Our work provides further support for using telmisartan to manipulate CAF populations in the solid tumour microenvironment to decrease collagen deposition and render tumours more responsive to current cancer therapies.