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.

CD73, an ecto-5′-nucleotidase (NT5E), serves as an immune checkpoint by generating adenosine (ADO), which suppresses immune activation through the A 2A receptor. Elevated CD73 levels in tumor tissues correlate with poor clinical outcomes. However, the crucial source of CD73 activity within the tumor microenvironment remains unspecified. Here, we demonstrate that cancer-associated fibroblasts (CAFs) constitute the prominent CD73 hi population in human colorectal cancers (CRCs) and two CD73 − murine tumor models, including a modified CRC. Clinically, high CAF abundancy in CRC tissues correlates strongly with elevated CD73 activity and poor prognosis. Mechanistically, CAF-CD73 expression is enhanced via an ADO-A 2B receptor-mediated feedforward circuit triggered by tumor cell death, which enforces the CD73-checkpoint. Simultaneous inhibition of A 2A and A 2B pathways with CD73-neutralization synergistically enhances antitumor immunity in CAF-rich tumors. Therefore, the strategic and effective targeting of both the A 2B-mediated ADO-CAF-CD73 feedforward circuit and A 2A-mediated immune suppression is crucial for improving therapeutic outcomes.

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e24046 Background: Immunotherapy (IO) is now an integral part of treatment for most patients with triple negative breast cancer (TNBC). The mechanism of action and associated side effects of IO differ significantly from conventional chemotherapy and patient comprehension of these novel treatments can be difficult to assess. Previous research has demonstrated that patient understanding of anti-cancer treatments is hindered by multiple barriers including education level and healthcare literacy. Standardized educational tools to improve patient comprehension of immunotherapy are integral to improving patient engagement with their treatment plan and providing informed consent. Methods: This is a prospective pilot study investigating the efficacy of standardized educational materials (2 animated videos and 1 pamphlet) to improve patient comprehension of IO. Patients with TNBC were recruited from Emory University between 2021-2022 and were asked three questions related to their understanding of the immune system, immunotherapy, and IO-related side effects before and after viewing the educational tools. Audio-recordings of the patients’ answers were coded as correct or incorrect by two independent reviewers using the video’s definitions as the standard. Clopper-Pearson method and exact McNemar’s test were used to calculate pre- and post-education correct definition rates and paired rates, respectively. Multivariate analyses were conducted investigating the impact of age, highest level of education, and race on patient comprehension. Results: 46 patients with TNBC were enrolled with mean age of 57 years (range 27-84 years). The majority of patients were Black (65%), while the remaining patients were Non-Hispanic White (30%) or unknown (5%). Highest level of education was reported as high school (13%), undergraduate (61%), and graduate school (26%). Comprehension of the terms "immune system" and "immunotherapy" significantly improved after viewing the patient educational material with an increase in correctly defining these terms from 50% to 89.1% (p-value < 0.01) and 41.3% to 82.6% (p-value < 0.01), respectively. Patients' ability to describe two or more side effects of IO also increased from 11% to 87% post-education (p-value < 0.01). Patients with graduate degrees had a 4.24 times greater odds of correctly answering the questions compared to those with undergraduate or high school degrees (p-value 0.057). There were no differences in patient comprehension by race or age. Conclusions: Patient education on novel therapeutics in cancer care including immunotherapy presents a challenge to providers given time constraints in clinic and lack of standardized educational resources. Through easily implemented patient education, we were able to significantly improve patient comprehension of immunotherapy and IO-related side effects in a diverse population of patients with TNBC.