Germline modifiers of the tumor immune microenvironment implicate drivers of cancer risk and immunotherapy response

Abstract

With the continued promise of immunotherapy for treating cancer, understanding how host genetics contributes to the tumor immune microenvironment (TIME) is essential to tailoring cancer screening and treatment strategies. Here, we study 1084 eQTLs affecting the TIME found through analysis of The Cancer Genome Atlas and literature curation. These TIME eQTLs are enriched in areas of active transcription, and associate with gene expression in specific immune cell subsets, such as macrophages and dendritic cells. Polygenic score models built with TIME eQTLs reproducibly stratify cancer risk, survival and immune checkpoint blockade (ICB) response across independent cohorts. To assess whether an eQTL-informed approach could reveal potential cancer immunotherapy targets, we inhibit CTSS, a gene implicated by cancer risk and ICB response-associated polygenic models; CTSS inhibition results in slowed tumor growth and extended survival in vivo. These results validate the potential of integrating germline variation and TIME characteristics for uncovering potential targets for immunotherapy.

Stochastic modelling of single-cell gene expression adaptation reveals non-genomic contribution to evolution of tumor subclones

“…The response of tumors derived from the parental B2905 cell line to ICB treatment was determined in a preclinical study described previously 34 . Briefly, mice bearing tumors grown from implanted parental B2905 cells were subjected to anti-CTLA-4 or control IgG treatment.…”

Ultrasound-Induced Gold Nanoparticle United with Acoustic Reprogramming of Macrophages for Enhanced Cancer Therapy

“…Solid tumors have a highly complex immune environment that is extensively infiltrated with immune cells. , Macrophages play a vital role in the TME because of their high numbers and intricate functions . TAMs could serve as an indicator of regional and systemic cues that promote tumor cell growth, survival, and migration .…”

Immune‐related adverse events in non‐small cell lung cancer: Occurrence, mechanisms and therapeutic strategies

“…Germline genetic factors exert significant influence on immune homeostasis and our immunological status 17,124 . The variability in the onset and severity of irAEs observed among patients receiving similar ICI agents can be partially attributed to germline genetic variation in immune function 17,124 .…”

“…Germline genetic factors exert significant influence on immune homeostasis and our immunological status 17,124 . The variability in the onset and severity of irAEs observed among patients receiving similar ICI agents can be partially attributed to germline genetic variation in immune function 17,124 . Recent research has demonstrated a correlation between polygenic germline risk for autoimmune conditions and the development of cutaneous and thyroid irAEs in NSCLC 125,126 .…”