Immune Exclusion in Cancer Immunotherapy

ABSTRACT Most patients with solid tumors do not benefit from immune-checkpoint inhibition, emphasizing the need to improve immunotherapy. We have demonstrated that the T cell-inflamed tumor microenvironment (TME), characterized by CD8+ T cells and type I/II interferon (IFN) gene expression, is an important cancer immunotherapy biomarker. Tumor mutational burden may also dictate response with some oncogenic pathways, such as WNT/β-catenin, known to mediate immune-exclusion and drive the non-T cell-inflamed TME. Our research group has nominated a core group of molecular targets associated with immune-exclusion centered at p38 MAPK. p38 is known to regulate macrophages and dendritic cells. However, our data are the first to describe a tumor cell-intrinsic role for p38 driving the non-T cell-inflamed TME. In this project, we will investigate tumor cell p38 signaling as a new mechanism of resistance to immunotherapy in carcinogen- associated head and neck squamous cell carcinoma (HNSCC), lacking infection by human papillomavirus (HPV). Our research aims are to (1) Establish a causal link between p38, non-T cell-inflamed tumors, and resistance to ICI in HPV- HNSCC (2) Determine the impact of tumor cell p38 MAPK spatial distribution on T cell infiltration in HPV− HNSCC (3) Validate and uncover co-activated mechanisms with p38 MAPK in HPV− HNSCC. We will leverage our lab’s unique role at the center of large-scale, multi-omic approaches as well as field-leading clinical trial and translational investigation. We will utilize 11 independent cohorts of patients with HPV- HNSCC. From the public domain, we will include RNAseq and image analysis from three cohorts, scRNAseq from one cohort, as well as cell line, drug sensitivity and FDA-approved drug databases. These analyses will be augmented for RNAseq, scRNAseq, and multispectral spatial imaging data from seven other cohorts organized by our team. These will include immunotherapy naïve patients and patients treated on a clinical trial we are leading of the p38 inhibitor ARRY-614 + nivolumab. We will utilize a combination of the computational, machine- and deep-learning analyses plus mechanistic murine experiements in four syngeneic models as well as in vitro validation studies to pursue our research. Our systemic approach has already nominated further molecular targets for combination approaches with p38 and immunotherapy. We will validate these and nominate further molecular targets to enhance cancer immunotherapy.