Tissue specificity and chromosomal alterations shape divergent immune programs in HRD tumors

Area of Science:

• Oncology
• Immunology
• Genomics

Background:

• Homologous recombination deficiency (HRD) activates pro-inflammatory pathways, suggesting its potential as a biomarker for combining immune checkpoint blockade (ICB) and PARP inhibition (PARPi).
• The impact of HRD on the tumor immune microenvironment across diverse cancer types is not fully understood.

Purpose of the Study:

• To investigate the heterogeneity of immune activity in HRD tumors across various cancer types.
• To classify HRD tumors into distinct immune archetypes to inform combinatorial therapy strategies.

Main Methods:

• Utilized a pan-cancer HRD classifier on over 10,000 tumor samples from The Cancer Genome Atlas (TCGA).
• Analyzed immune activity, including innate and adaptive immune pathways, senescence, angiogenesis, and adenosine signaling.
• Assessed large-scale loss-of-heterozygosity (LOH) at key immune loci and oncogene amplifications.

Main Results:

• HRD tumors exhibited significant immune landscape heterogeneity.
• Breast, ovarian, and endometrial HRD tumors showed elevated inflammation with activated immune pathways and senescence hallmarks.
• Lung, head and neck, and melanoma HRD tumors displayed suppressed inflammation, immune escape mechanisms (e.g., LOH at IFNA/B, STING, HLA), and oncogene amplifications.

Conclusions:

• HRD tumors can be categorized into two immune archetypes: immune-inflamed and immune-evasive.
• These archetypes are associated with chromosomal instability and cancer lineage.
• The findings provide a basis for biomarker-driven selection of patients for ICB/PARPi combination therapies.