Dadey, R. | Search bioRxiv

bioRxiv2026

Integrative multi-omic analysis identifies tumor-intrinsic p38 as a driver of immune exclusion in human epithelial cancers

Patients with tumors not responding to immune-checkpoint inhibition (ICI) often harbor a non-T cell-inflamed tumor microenvironment, characterized by the absence of IFN-{gamma}-associated CD8+ T cells and dendritic cell activation. While the role of p38 mitogen-activated protein kinases (MAPKs) in regulating dendritic and myeloid cells is established, the tumor-intrinsic immunomodulatory function of p38 remains underexplored. Here, we identify tumor cell-intrinsic p38 signaling as a target candidate associated with immune exclusion and reduced immunotherapy response. In human papillomavirus-negative head and neck squamous carcinoma (HNSCC), molecular analysis of 395 tumor tissues revealed a p38-centered network enriched in non-T cell-inflamed tumors. Multi-cancer single-cell RNA sequencing analysis of over 200,000 cells further identifies p38 activation as a potential immune-exclusion program across multiple epithelial tumor types, including HNSCC and lung squamous cell carcinoma (LUSC), supported by tissue validation in [~]250 human biospecimens using multispectral imaging and digital spatial profiling. Functional studies demonstrate that p38 knockdown or pharmacologic inhibition in HNSCC and LUSC cell lines increases T cell migration, with CXCL16 identified as a chemokine mediator in vitro; neutralization of CXCL16 attenuated this effect. Together, these findings identify tumor-intrinsic p38 activation as a driver of immune exclusion in epithelial cancers and support its potential as a therapeutic target to overcome immunotherapy resistance.

Cancer Biology↗

bioRxiv2020

Systemic immune dysfunction in cancer patients driven by IL6 and IL8 induction of an inhibitory receptor module in peripheral CD8+ T cells

Many cancer patients do not develop a durable response to the current standard of care immunotherapies despite substantial advances in targeting immune inhibitory receptors1-5. A potential compounding issue, which may serve as an unappreciated, dominant resistance mechanism, is an inherent systemic immune dysfunction that is often associated with advanced cancer6-12. Minimal response to inhibitory receptor (IR) blockade therapy and increased disease burden have been associated with peripheral CD8+ T cell dysfunction, characterized by suboptimal T cell proliferation and chronic expression of IRs (eg. Programmed Death 1 [PD1] and Lymphocyte Activation Gene 3 [LAG3])13, 14. Here, we demonstrate that up to a third of cancer patients express robust intracellular LAG3 (LAG3IC), but not surface LAG3 (LAG3SUR), in peripheral CD8+ T cells compared to CD4+ T cells and regulatory T cells (Tregs). LAG3IC is associated with: (i) expression of a LAG3IC-dominant IR module that includes PD1IC, NRP1IC, CD39IC, and TIGITIC; (ii) decreased CD8+ but not CD4+ T cell function that can be reversed by anti-LAG3 (and/or anti-PD1), despite limited constitutive surface IR expression; and (iii) poor disease prognosis. Systemic immune dysfunction is restricted to CD8+ T cells, including a high percentage of peripheral naive CD8+ T cells, indicating a TCR-independent mechanism that is driven by the cytokine IL6 and the chemokine IL8. Thus, the combination of an increased LAG3-dominant IR module and elevated systemic IL6 and/or IL8 may serve as predictive biomarkers and increase the possibility that cancer patients will benefit from therapeutic combinations targeting these systemic cytokines in the setting of PD1 and/or LAG3 blockade.

cancer biology↗